US5393762A - Pharmaceutical agents for treatment of emesis - Google Patents

Pharmaceutical agents for treatment of emesis Download PDF

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Publication number
US5393762A
US5393762A US08/072,629 US7262993A US5393762A US 5393762 A US5393762 A US 5393762A US 7262993 A US7262993 A US 7262993A US 5393762 A US5393762 A US 5393762A
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United States
Prior art keywords
phenylpiperidine
methoxybenzylamino
phenyl
alkyl
cis
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US08/072,629
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Manoj C. Desai
John A. Lowe, III
John W. Watson
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Zoetis LLC
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Pfizer Inc
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Assigned to PFIZER INC. reassignment PFIZER INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DESAI, MANOJ C., LOWE, JOHN A., III, ROSEN, TERRY A., WATSON, JOHN W.
Priority to US08/072,629 priority Critical patent/US5393762A/en
Priority to TW083103232A priority patent/TW318791B/zh
Priority to PT94303467T priority patent/PT627221E/en
Priority to DE69429208T priority patent/DE69429208T2/en
Priority to AT94303467T priority patent/ATE209490T1/en
Priority to DK94303467T priority patent/DK0627221T3/en
Priority to EP94303467A priority patent/EP0627221B1/en
Priority to ES94303467T priority patent/ES2164088T3/en
Priority to IL10980294A priority patent/IL109802A/en
Priority to JP6121042A priority patent/JP2671972B2/en
Priority to CA002124990A priority patent/CA2124990C/en
Priority to MYPI94001422A priority patent/MY115310A/en
Priority to RU94020410A priority patent/RU2135179C1/en
Priority to AU64521/94A priority patent/AU666077B2/en
Priority to KR1019940012527A priority patent/KR100190729B1/en
Priority to CN94106917A priority patent/CN1100535C/en
Priority to HU9401676A priority patent/HU222243B1/en
Priority to NZ260674A priority patent/NZ260674A/en
Priority to ZA943896A priority patent/ZA943896B/en
Publication of US5393762A publication Critical patent/US5393762A/en
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Assigned to AH USA 42 LLC reassignment AH USA 42 LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PFIZER INC.
Assigned to ZOETIS LLC reassignment ZOETIS LLC CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: AH USA 42 LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a method of treating or preventing emesis in mammals, including humans, using certain quinuclidine derivatives, piperidine derivatives, azanorbornane derivatives, ethylene diamine derivatives and related compounds.
  • the pharmaceutically active compounds employed in this invention are substance P receptor antagonists.
  • European Patent Application 533280A1 published Mar. 24,1993, refers to the use of substance P antagonists in the treatment of emesis.
  • This invention relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound that is a substance P receptor antagonist, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such condition.
  • This invention also relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula ##STR1## wherein A is a ring system selected from phenyl, naphthyl, thienyl, quinolinyl and indolinyl, and wherein the sidechain containing NR 2 R 3 is attached to a carbon atom of ring system A;
  • AA is an aryl group selected from phenyl, naphthyl, thienyl, dihydroquinolinyl and indolinyl, and wherein the sidechain containing NR 2 R 3 is attached to a carbon atom of AA;
  • W 1 is hydrogen, halo or (C 1 -C 6 ) alkyl, S--(C 1 -C 3 )alkyl, halo or (C 1 -C 6 ) alkoxy optionally substituted with from one to three fluorine atoms.
  • W is hydrogen, (C 1 -C 6 )alkyl optionally substituted with from one to three fluorine atoms, --S(O) v --(C 1 -C 6 ) alkyl wherein v is zero, one or two, halo or (C 1 -C 6 )alkoxy optionally substituted with from one to three fluorine atoms;
  • R is a 4, 5 or 6 membered heterocyclic ring containing from one to three heteroatoms selected from oxygen, nitrogen and sulfur (e.g., thiazolyl, azetidinyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isothiazolyl, imidazolyl, isoxazolyl, or oxazolyl) wherein said heterocyclic ring may contain from zero to three double bonds and may optionally be substituted with one or more substituents, preferably one or two substituents, independently selected from (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms and C 1 -C 6 ) alkoxy optionally substituted with from one to three fluorine atoms;
  • R 1 is selected from amino, (C 1 -C 6 )alkylamino, di-(C 1 -C 6 )alkylamino, --S(O) v --(C 1 -C 10 )-alkyl wherein v is zero, one or two, --S(O) v -aryl wherein v is zero, one or two, --O-aryl, --SO 2 NR 4 R 5 wherein each of R 4 and R 5 is, independently, (C 1 -C 6 )alkyl, or R 4 and R 5 , together with the nitrogen to which they are attached, form a saturated ring containing one nitrogen and from 3 to 6 carbons, ##STR2## wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, --N(SO 2 --(C 1 -C 10 )alkyl) 2 and ##STR3## and wherein the aryl moieties of said --S(O) v -aryl
  • R 1 is a group having the formula ##STR5## wherein a is 0, 1 or 2 and the asterisk represents a position meta to the R 2 R 3 NCH 2 side chain;
  • X is selected from ⁇ CH--, --CH 2 --, --O--, --S--, --SO--, --SO 2 --, --N(R 4 )--, --NH--, ⁇ N--, --CH[(C 1 -C 6 )alkyl]--, ⁇ C[(C 1 -C 6 )alkyl]--, --CH(C 6 H 5 )-- and ⁇ C(C 6 H 5 )--;
  • Y is selected from C ⁇ O, C ⁇ NR 4 , C ⁇ S, ⁇ CH--, --CH 2 --, ⁇ C[(C 1 -C 5 )alkyl]--, --CH[(C 1 -C 6 )alkyl]--, ⁇ C(C 6 H 5 )--, --CH (C 6 H 5 )--, ⁇ N--, --NH--, --N(R 4 )--, ⁇ C(halo)--, ⁇ C(OR 4 )--, ⁇ C(SR 4 )--, ⁇ C(NR 4 )--, --O--, --S--and SO 2 , wherein the phenyl moieties of said ⁇ C(C 6 H 5 )-- and --CH(C 6 H 5 )-- may optionally be substituted with from one to three substituents independently selected from trifluoromethyl and halo, and wherein the alkyl moieties of said ⁇ [(C 1
  • Z is selected from ⁇ CH--, --CH 2 --, ⁇ N--, --NH--, --S--, --N(R 4 )--, ⁇ C(C 6 H 5 )--, --CH(C 6 H 5 )--, ⁇ C[(C 1 -C 6 )alkyl]-- and --CH[(C 1 -C 6 )alkyl]--;
  • X 1 is hydrogen, (C 1 -C 10 ) alkoxy optionally substituted with from one to three flourine atoms or (C 1 -C 10 ) alkyl optionally substituted with from one to three fluorine atoms;
  • X 2 and X 3 are independently selected from hydrogen, halo, nitro, (C 1 -C 10 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 10 ) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, hydroxy, phenyl, cyano, amino, (C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )alkylamino, ##STR6## hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, ##STR7## R 4 is (C 1 -C 6 ) alkyl or phenyl; R 2 is hydrogen or --CO 2 (C 1 -C 10 ) alkyl;
  • R 3 is selected from ##STR8## wherein R 6 and R 10 are independently selected from furyl, thienyl, pyridyl, indolyl, biphenyl and phenyl, wherein said phenyl may optionally be substituted with one or two substituents independently selected from halo, (C 1 -C 10 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 10 ) alkoxy optionally substituted with from one to three fluorine atoms, carboxy, benzyloxycarbonyl and (C 1 -C 3 ) alkoxy-carbonyl;
  • R 7 is selected from (C 3 -C 4 ) branched alkyl, (C 5 -C 6 ) branched alkenyl, (C 5 -C 7 ) cycloalkyl, and the radicals named in the definition of R 6 ;
  • R 8 is hydrogen or (C 1 -C 6 ) alkyl
  • R 9 and R 19 are independently selected from phenyl, biphenyl, naphthyl, pyridyl, benzhydryl, thienyl and furyl, and R 9 and R 19 may optionally be substituted with from one to three substituents independently selected from halo, (C 1 -C 10 ) alkyl optionally substituted with from one to three fluorine atoms and (C 1 -C 10 ) alkoxy optionally substituted with from one to three fluorine atoms;
  • Y 1 is (CH 2 ) 1 wherein 1 is an integer from one to three, or Y 1 is a group of the formula ##STR9##
  • Z 1 is oxygen, sulfur, amino, (C 1 -C 6 )alkylamino or (CH 2 ) n wherein n is zero, one or two;
  • x is an integer from zero to four;
  • y is an integer from zero to four;
  • z is an integer from one to six, wherein the ring containing (CH 2 ) z may contain from zero to three double bonds, and one of the carbons of (CH 2 ) z may optionally be replaced by oxygen, sulfur or nitrogen;
  • o is two or three
  • p is zero or one
  • r is one, two or three;
  • R 11 is thienyl, biphenyl or phenyl optionally substituted with one or two substituents independently selected from halo, (C 1 -C 10 ) alkyl optionally substituted with from one to three fluorine atoms and (C 1 -C 10 ) alkoxy optionally substituted with from one to three fluorine atoms;
  • X 4 is (CH 2 ) q wherein q is an integer from 1 to 6, and wherein any one of the carbon-carbon single bonds in said (CH 2 ) q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH 2 ) q may optionally be substituted with R 14 , and wherein any one of the carbon atoms of said (CH 2 ) q may optionally be substituted with R 15 ;
  • m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH 2 ) m , wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH 2 ) m , chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH 2 ) m , may optionally be substituted with R 17 ;
  • R 12 is a radical selected from hydrogen, (C 1 -C 6 ) straight or branched alkyl, (C 3 -C 7 )cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C 2 -C 6 )alkyl, benzhydryl and benzyl, wherein the point of attachment on R 12 is a carbon atom unless R 12 is hydrogen, and wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C 2 -C 6 )alkyl and
  • R 13 is hydrogen, phenyl or (C 1 -C 6 )alkyl
  • R 12 and R 13 together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms that is neither the point of attachment of the spiro ring nor adjacent to it may optionally be replaced by oxygen, nitrogen or sulfur;
  • R 14 and R 15 are each independently selected from hydrogen, hydroxy, halo, amino, oxo ( ⁇ O), cyano, hydroxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino, ##STR11## and the radicals set forth in the definition of R 12 ;
  • R 16 is ##STR12## NHCH 2 R 18 , SO 2 R 18 , GR 20 CO 2 H or one of the radicals set forth in any of the definitions of R 12 , R 14 and R 15 ;
  • R 17 is oximino ( ⁇ NOH) or one of the radicals set forth in any of the definitions of R 12 , R 14 and R 15 ; and
  • R 18 is (C 1 -C 6 )alkyl, hydrogen, phenyl or phenyl (C 1 -C 6 )alkyl;
  • G is selected from the group consisting of CH 2 , nitrogen, oxygen, sulfur and carbonyl;
  • R 20 is a monocyclic or bicyclic heterocycle selected from the group consisting of pyrimidinyl, benzoxazolyl, 2,3-dihydro-3-oxobenzisosulfonazol-2-yl, morpholin-1-yl, thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl, isoquinolinyl, furyl, pyridyl, isothiazolyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl, thienyl, and groups of the formulae ##STR13## wherein B and D are selected from carbon, oxygen, and nitrogen, and at least one of B and D is other than carbon; E is carbon or nitrogen; n is an integer from 1 to 5; and any one of the carbons of the (CH 2 ) n or (CH 2 ) n+1 may be optionally substituted
  • each of R 14 and R 15 is independently selected from hydrogen, fluoro, (C 1 -C 6 )alkyl, hydroxy-(C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, or R 14 and R 15 , together with the carbon to which they are attached, form a (C 3 -C 6 ) saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; (d) R 12 and R 13 cannot both be hydrogen; (e) when R 14 or R 15 is attached to a carbon atom of X 4 or (CH 2 ) y that is adjacent
  • the fused bicyclic nucleus of compounds of the formula Ib to which W and the --CN 2 NR 2 R 3 sidechain are attached may be, but is not limited to one of the following groups: benzoxazolyl, benzthiazolyl, benzimidazolyl, benzisoxazolyl, benzoisothiazolyl, indazolyl, indolyl, isoquinolinyl, benzofuryl, benzothienyl, oxindolyl, benzoxazolinonyl, benzthiazolinonyl, benzimidazolinonyl, benzimidazoliniminyl, dihydrobenzothienyl-S,S-dioxide, benztriazolyl, benzthiadiazolyl, benzoxadiazolyl, and quinazolinyl.
  • Preferred embodiments of this invention include methods of treating or preventing emesis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (1) through (46)
  • R 3 is a group of the formula VII or VIII, "a cis configuration", as used herein, means that the non-hydrogen substituent at position "3" is cis to R 2 ).
  • R 3 is a group of the formula III, VII or IX;
  • R 2 is hydrogen;
  • A is phenyl or indolinyl;
  • W is (C 1 -C 3 )alkoxy optionally substituted with from one to five fluorine atoms; and
  • R is thiazolyl, imidazolyl, thiadiazolyl, pyrrolyl or oxazolyl, and R may optionally be substituted with one or two (C 1 -C 3 ) alkyl moieties.
  • R 3 is a group of the formula III and R 9 is benzhydryl
  • R 3 is a group of the formula VII, R 12 is phenyl, each of R 13 , R 14 , R 15 and R 16 is hydrogen, m is zero and X 4 is --(CH 2 ) 3 --
  • R 3 is a group of the formula IX, r is two and R 19 is benzhydryl.
  • R 3 is a group of the formula III wherein the substituents at positions "2" and “3" of the nitrogen containing ring are in the cis configuration, R 9 is benzhydryl and A is phenyl; or (b) R 3 is a group of the formula VII wherein R 12 and the substituent at position "3" of the nitrogen containing ring are in the cis configuration, A is phenyl, R 12 is phenyl each of R 2 , R 13 , R 14 , R 15 and R 16 is hydrogen, m is zero, W is methoxy or isopropoxy, X 4 is --(CH 2 ) 3 -- and R is thiazolyl, imidazolyl, pyrrolyl, oxazolyl or thiadiazolyl.
  • R 3 is a group of the formula II, III, VII or IX; R 2 is hydrogen; ring AA is phenyl or indolinyl; W 1 is (C 1 -C 3 )alkoxy optionally substituted with from one to three fluorine atoms; and R 1 is S(O) v --(C 1 -C 10 )alkyl wherein v is zero, one or two, S(O) v -aryl wherein v is zero, one or two, --O---aryl, ##STR14## wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, --N(SO 2 --(C 1 -C 10 )alkyl) 2 or ##STR15## wherein said aryl is phenyl or benzyl and may optionally be substituted with from one to three substituents independently selected from (C 1 -C 6 )alkyl, (C 1
  • R 3 is a group of the formula VII wherein R 12 and the substituent at position "3" of the nitrogen containing ring are in the cis configuration, ring AA is phenyl, R 12 is phenyl, each of R 2 , R 13 , R 14 , R 15 and R 16 is hydrogen, m is zero X 4 is --(CH 2 ) 2 -- or --(CH 2 ) 3 -- and R 1 is selected from S(O) v --(C 1 -C 10 ) alkyl wherein v is zero one or two and ##STR16## and di-(C 1 -C 6 ) alkylamino.
  • a compound of the formula Ic wherein R 3 is a group of the formula VII, m is zero, each of R 13 , R 15 , R 16 and R 17 is hydrogen, R 12 is phenyl, R 14 is ##STR20## ring AA is phenyl, W 1 is (C 1 -C 3 ) alkoxy and R 1 is selected from (C 1 -C 15 )alkyl, --SCH 3 , SO 2 CH 3 , SOCH 3 , (C 1 -C 6 )alkylamino and di-(C 1 -C 6 )alkyl-amino.
  • R 6 , R 10 , R 11 and R 13 are phenyl
  • R 8 is hydrogen
  • R 9 is phenyl optionally substituted with chlorine, fluorine, (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms or (C 1 -C 6 ) alkoxy optionally substituted with from one to three fluorine atoms
  • m is 0 and n is 3 or 4.
  • R 3 is a group of the formula VIII wherein y is zero, x is zero or one, z is three or four, m is zero and R 12 is phenyl or substituted phenyl.
  • R 3 is a group of the formula VII, R 6 , R 14 , R 13 , R 16 and R 15 are hydrogen, R 12 is phenyl, X 1 is 2-methoxy, X 2 and X 3 are independently selected from hydrogen, chlorine, fluorine, methyl, (C 1 -C 6 )alkoxy and trifluoromethane, m is 0 and q is 3 or 4.
  • This invention also relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound having the formula ##STR22## wherein W is Y or X(CH 2 ) n ; Y is optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl or optionally substituted (C 3 -C 8 )cycloalkyl;
  • X is optionally substituted (C 1 -C 6 )alkoxy, CONR 1 R 2 , CO 2 R 1 , CHR 1 OR 2 , CHR 1 NR 2 R 3 , COR 1 , CONR 1 OR 2 or optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and n is an integer from zero to six;
  • Ar 1 , Ar 2 and Ar 3 are each, independently, optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl;
  • R 1 , R 2 and R 3 are independently selected from hydrogen, optionally substituted C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 8 )cycloalkyl, optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and optionally substituted (C 1 -C 5 )heterocyclic groups, wherein said heterocyclic groups are selected from pyrrolidino, piperidino, morpholino, piperazinyl and thiamorpholino;
  • substituents on the foregoing substituted alkyl, alkenyl, cycloalkyl and alkoxy groups are independently selected from halo, nitro, amino, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, trifluoromethyl and trifluoromethoxy;
  • substituents on the foregoing substituted (C 1 -C 5 ) heterocyclic groups are attached to a sulfur or nitrogen atom on the ring and are independently selected from oxygen, di-oxygen and (C 1 -C 4 )alkyl;
  • substituents on said substituted Ar 1 groups are independently selected from (C 1 -C 6 )alkyl optionally substituted with from one to three halo groups, (C 1 -C 6 )alkoxy optionally substituted with from one to three halo groups, (C 1 -C 6 )alkylsulfinyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylsulfonyl, (C 1 -C 6 )alkylsulfonylamino, and di-(C 1 -C 6 )alkylamino wherein one or both of the alkyl groups may be optionally substituted with a (C 1 -C 6 )alkylsulfonyl, or (C 1 -C 6 )alkylsulfinyl group;
  • substituents on said substituted Ar 2 and Ar 3 groups are independently selected from (C 1 -C 4 )alkyl, (C l -C 4 )alkoxy, (C 1 -C 4 )alkylthio, (C 1 -C 4 )alkylsulfinyl, di-(C 1 -C 4 )alkylamino, trifluoromethyl and trifluoromethoxy; with the proviso that when Y is unsubstituted or is substituted with (C 1 -C 4 )alkyl, it is attached to the 4- or 6-position of the quinuclidine ring;
  • Preferred embodiments of this invention include methods of treating or preventing emesis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (48) through (53) below, that is effective in treating or preventing such condition.
  • a compound of the formula X, wherein W is X(CH 2 ) n .
  • a compound of the formula X, wherein W is Y.
  • a compound of the formula X, wherein Ar 1 is substituted aryl and W is Y.
  • a compound of the formula X, wherein Ar 1 is mono-, di- or tri-substituted phenyl and W is Y.
  • This invention also relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound having the formula ##STR23## wherein R 1 is selected from hydrogen, (C 1 -C 6 ) straight or branched alkyl, (C 3 -C 7 ) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, biphenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C 2 -C 6 ) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the pheny
  • R 3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C 3 -C 7 ) cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 6 ) alkoxy optionally substituted with from one to three fluorine
  • R 7 and R 8 are independently selected from hydrogen, (C 1 -C 3 )alkyl and phenyl;
  • R 9 is selected from methyl, hydroxyethyl, ##STR26##
  • R 14 R 15 NCO 2 CH 2 --, R 16 OCO 2 CH 2 --, (C 1 -C 4 )alkyl-CO 2 CH 2 --, --CONR 17 R 18 , R 17 R 18 NCO 2 --, R 19 OCO 2 --, C 6 H 5 CH 2 CO 2 CH 2 --, C 6 H 5 CO 2 CH 2 --, (C 1 -C 4 )alkyl-CH(OH)--, C 6 H 5 CH(OH)--, C 6 H 5 CH 2 CH(OH)--, CH 2 halo, R 20 SO 2 OCH 2 , --CO 2 R 16 and R 21 CO 2 --;
  • R 10 and R 11 are independently selected from hydrogen, (C 1 -C 3 ) alkyl and phenyl;
  • R 12 is hydrogen, benzyl or a group of the formula ##STR27## wherein m is an integer from zero to twelve, and any one of the carbon-carbon single bonds of (CH 2 ) m , wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH 2 ) m chain, may optionally be replaced by a carbon-carbon double or triple bond, and any one of the carbon atoms of (CH 2 ) m may optionally be substituted with R 23 ;
  • R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 24 are independently selected from hydrogen, (C 1 -C 3 )alkyl and phenyl;
  • R 22 and R 23 are independently selected from hydrogen, hydroxy, halo, amino, carboxy, carboxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino, di-(C 1 -C 6 )alkylamino, (C 1 - 6 )alkoxy, ##STR28## (C 1 -C 6 ) straight or branched alkyl, (C 3 -C 7 ) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C 2 -C 6 )alkyl, benzhydryl and benz
  • R 9 together with the carbon to which it is attached, the nitrogen of the pyrrolidine ring, the carbon to which R 7 is attached and the carbon to which R 5 and R 6 are attached form a second pyrrolidine ring; with the proviso that when R 9 together with the carbon to which it is attached the nitrogen of the pyrrolidine ring, the carbon to which R 7 is attached and the carbon to which R 5 and R 6 are attached, form a second pyrrolidine ring (thus forming a bicyclic structure containing a bridgehead nitrogen), either R 12 is absent or R 12 is present and the nitrogen of the second pyrrolidine ring is positively charged; or a pharmaceutically acceptable salt of such compound, effective in treating or preventing such condition.
  • Preferred embodiments of this invention include methods of treating or preventing emesis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (55) through (59) below, that is effective in treating or preventing such condition.
  • R 1 is diphenylmethyl
  • R 3 is aryl selected from phenyl or indanyl wherein each of said aryl groups may be optionally substituted with one, two or three substituents
  • each of R 5 , R 6 , R 7 , R 8 , R 10 , and R 11 is hydrogen
  • R 9 is selected from hydroxymethyl, methoxymethyl, --CO 2 R 16 , --CONR 17 R 18 , R 14 R 15 NCO 2 CH 2 --, R 16 OCO 2 CH 2 --, (C 1 -C 4 )alkyl-CO 2 CH 2 --, C 6 H 5 CH 2 CO 2 CH 2 --, --CH 2 halo and R 20 SO 2 OCH 2 --
  • R 12 is hydrogen or benzyl.
  • R l is phenyl
  • R 3 is aryl selected from phenyl or indanyl wherein each of said aryl groups may be optionally substituted with one, two or three substituents
  • each of R 5 , R 6 , R 7 , R 8 , R 10 , and R 11 is hydrogen
  • R 9 is selected from hydroxymethyl, methoxymethyl
  • --CO 2 R 18 --CONR 17 R 18
  • R 14 R 15 NCO 2 CH 2 CH 2 --, R 16 OCO 2 CH 2 --, (C 1 -C 4 )alkyl-CO 2 CH 2 --, --CH 2 halo
  • R 12 is hydrogen or benzyl.
  • This invention also relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula ##STR31## wherein R 1 is hydrogen, (C 1 -C 8 ) alkyl, a saturated (C 6 -C 10 ) carbocyclic ring system containing two fused rings, a saturated (C 6 -C 10 ) carbocyclic bridged ring system containing two rings, or benzyl wherein the phenyl moiety of said benzyl may optionally be substituted with one or more substituents independently selected from halo, (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms and (C 1 -C 8 ) alkoxy optionally substituted with from one to three fluorine atoms;
  • R 2 is hydrogen, benzyl or a group of the formula ##STR32## wherein m is an integer from zero to twelve, and any one of the carbon-carbon single bonds of (CH 2 ) m , wherein both carbon atoms of such bond are bonded to each other and to another carbon atom of the (CH 2 ) m chain, may optionally be replaced by a carbon-carbon double or triple bond, and any one of the carbon atoms of (CH 2 ) m may optionally be substituted with R 9 ;
  • R 8 and R 9 are independently selected from hydrogen, hydroxy, halo, amino, carboxy, carboxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino, di-(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy, ##STR33## straight or branched alkyl, (C 3 -C 7 ) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C 2 -C 6 )alkyl, benzhydryl and benzyl, wherein each of said
  • R 1 and R 2 together with the nitrogen to which they are attached, form a saturated or unsaturated monocyclic ring containing from three to eight carbon atoms, a fused bicyclic ring containing from six to ten carbon atoms, or a saturated bridged ring system containing from six to ten carbon atoms;
  • R 4 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having from three to seven carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C 3 -C 7 ) cycloalkyl may optionally be substituted with one, two or three substituents, each of said substituents being independently selected from halo, nitro, (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 6 ) alkoxy optionally substituted with from one to three flu
  • R 5 is hydrogen, (C 1 -C 6 ) alkyl, or phenyl optionally substituted with one or more substituents independently selected from halo, (C 1 -C 6 )alkyl optionally substituted with from one to three fluorine atoms and (C 1 -C 6 )alkoxy optionally substituted with from one to three fluorine atoms;
  • R 6 is selected from hydrogen, (C 1 -C 6 ) straight or branched alkyl, (C 3 -C 7 ) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, biphenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C 2 -C 6 ) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C 2 -C 6 ) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro
  • R 12 is hydrogen, (C 1 -C 3 )alkyl or phenyl
  • Preferred embodiments of this invention include methods of treating or preventing emesis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (60) through (62) below, that is effective in treating or preventing such condition.
  • R 2 is hydrogen or R 2 and R 1 together with the nitrogen to which they are attached, form a monocyclic ring containing five to seven carbon atoms;
  • R 3 is hydrogen, methyl or phenyl;
  • R 5 is hydrogen;
  • R 4 is phenyl or indanyl, wherein said phenyl or indanyl may optionally be substituted with from one to three substituents independently selected from halo, nitro, (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 6 ) alkoxy, trihaloalkoxy (e.g., trifluoromethoxy), (C 1 -C 6 ) alkylamino, --C (O)NH--(C 1 -C 8 )alkyl, (C 1 -C 6 )alkyl-C(O)--, --C(O)--O--(C 1 -C 6 )al
  • R 1 is alkyl
  • R 6 is unsubstituted phenyl
  • R 4 is a monosubstituted or disubstituted aryl group that is substituted at the C-2 position with an alkoxy group or substituted at the C-5 position with an alkyl, alkoxy or trihaloalkoxy group, or substituted in such manner at both C-2 and C-5 positions (i.e., with an alkoxy group at the C-2 position and an alkyl, alkoxy or trihaloalkoxy group at the C-5 position), and each of R 2 , R 3 and R 5 is hydrogen.
  • This invention also relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula ##STR37## wherein R 1 is cycloalkyl having from five to seven carbon atoms, pyrrolyl, thienyl, pyridyl, phenyl or substituted phenyl, wherein said substituted phenyl is substituted with from one to three substituents independently selected from fluorine, chlorine, bromine, trifluoromethyl, alkyl having from one to three carbon atoms, alkoxy having from one to three carbon atoms, carboxy, alkoxycarbonyl having from one to three carbon atoms in the alkoxy moiety and benzyloxycarbonyl;
  • R 2 is furyl, thienyl, pyridyl, indolyl, biphenyl, phenyl or substituted phenyl, wherein said substituted phenyl is substituted with one or two substituents independently selected from fluorine, chlorine, bromine, trifluoromethyl, alkyl having from one to three carbon atoms, alkoxy having from one to three carbon atoms, carboxy, alkoxycarbonyl having from one to three carbon atoms in the alkoxy moiety and benzyloxycarbonyl; and
  • R 3 is thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl, or a pharmaceutically acceptable salt of such compound, effective in treating or preventing such condition.
  • Preferred embodiments of this invention include methods of treating or preventing emesis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (63) through (65) below, that is effective in treating or preventing such condition.
  • This invention also relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula ##STR38## wherein m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH 2 ) m , wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH 2 ) m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH 2 ) m may optionally be substituted with R 8 ;
  • w is an integer from 0 to 2;
  • y is an integer from 1 to 4.
  • z is an integer from 1 to 4, and wherein any one of the carbon atoms of said (CH 2 ) z may optionally be substituted with
  • R 1 is hydrogen or (C 1 -C 8 )alkyl optionally substituted with hydroxy, alkoxy or fluoro;
  • R 2 is a group selected from hydrogen, (C 1 -C 6 )straight or branched alkyl, (C 3 -C 7 )cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, indanyl, and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl(C 2 -C 6 )alkyl, benzhydryl and benzyl, wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl and wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzy
  • R 3 is aryl selected from phenyl, indanyl, and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C 3 -C 7 )cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, (C 1 -C 6 )alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 6 )alkoxy optionally substituted with from one to three fluorine
  • R 8 is oximino ( ⁇ NOH) or one of the groups set forth in any of the definitions of R 2 and R 4 ;
  • R 9 is (C 1 -C 6 )alkyl, hydrogen, phenyl or phenyl (C 1 -C 6 )alkyl;
  • Preferred embodiments of this invention include methods of treating or preventing emesis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (66) through (68) below, that is effective in treating or preventing such condition.
  • R 2 is a radical selected from hydrogen, phenyl, naphthyl and benzhydryl; wherein each of said phenyl, naphthyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C 1 -C 6 ) alkyl, (C 1 -C 6 )alkoxy, trifluoromethyl, amino, ##STR43## and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl.
  • R 4 is independently selected from hydrogen, hydroxy, halo, amino, oxo ( ⁇ O), nitrile, (C 1 -C 6 )alkylamino, di-(C 1 -C 6 )alkylamino, (C 1 -C 6 )alkoxy, ##STR45## (C 1 -C 6 )alkyl and phenyl.
  • This invention also relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal a compound of the formula ##STR46## wherein X 1 is C 1 -C 5 alkoxy or halosubstituted (C 1 -C 5 )alkoxy;
  • X 2 is hydrogen, halogen, (C 1 -C 5 )alkyl, (C 2 -C 5 )alkenyl, (C 2 -C 5 )alkynyl, (C 1 -C 5 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 5 ) alkylsulfinyl, (C 1 -C 5 )alkylsulfonyl, halosubstituted (C 1 -C 5 ) alkyl, halosubstituted (C 1 -C 5 )alkoxy, (C 1 -C 8 )alkylamino, dialkylamino having from 1 to 5 carbon atoms in each alkyl moiety, (C 1 -C 8 )alkylsulfonylamino (which may be substituted by halogen), N--(C 1 -C 5 )alkyl-N--(C 1 -C 5
  • Ar 1 and Ar 2 are each, independently, thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl;
  • A is Y--(CH 2 ) m --CH(R 2 )--(CH 2 ) n --NR 1 --;
  • R 1 is hydrogen, (C 1 -C 5 )alkyl, benzyl or --(CH 2 ) p --Y;
  • R 2 is hydrogen, (C 1 -C 5 )alkyl (which may be substituted by a substituent selected from the group consisting of hydroxy, amino, methylthio and mercapto), benzyl, 4-hydroxybenzyl, 3-indolylmethyl or --(CH 2 ) p --Y;
  • Y is --CN, --CH 2 Z or --COZ
  • Z is hydroxy, amino, (C 1 -C 5 )alkoxy, (C 1 -C 5 )alkylamino or dialkylamino having from 1 to 5 carbon atoms in each alkyl moiety;
  • n and p are each, independently, 0, 1, 2 or 3;
  • R 1 and R 2 may be connected to form a ring
  • Preferred embodiments of this invention include methods of treating or preventing emesis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraph (69) below, that is effective in treating or preventing such condition.
  • This invention also relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula ##STR47## wherein R 1 is phenyl optionally substituted with one or more substituents, preferably with from one to three substituents, independently selected from hydrogen, halo, nitro, (C 1 -C 10 )alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 10 )alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, hydroxy, phenyl, cyano, amino, (C 1 -C 6 )-alkylamino, ##STR48## (C 1 -C 4 )alkoxy (C 1 -C 4 )alkyl, --S(O) v -- (C 1 -C 10 )-alkyl wherein v is zero, one or two, --S (
  • alkyl moieties may optionally be substituted with from one to three fluorine atoms, --N(SO 2 --(C 1 -C 10 )alkyl) 2 and ##STR50## and wherein the aryl moieties of said --S(O) v -aryl, --O-aryl and ##STR51## are independently selected from phenyl and benzyl and may optionally be substituted with from one to three substituents independently selected from (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy and halo;
  • R 1 is phenyl substituted with a group having the formula ##STR52## wherein a is 0, 1 or 2 and the asterisk represents a position meta to the point of attachment of R 1 ;
  • R 2 is selected from (C 1 -C 6 ) straight or branched alkyl, (C 3 -C 7 )cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C 2 -C 6 )alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C 2 -C 6 )alkyl and benzhydryl may optionally be substituted with one or more substituents, preferably with from one to three substituents,
  • m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH 2 ) m , wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH 2 ) m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH 2 ) m , may optionally be substituted with R 4 ;
  • R 3 is selected from ##STR54## NHCH 2 R 8 , SO 2 R 8 , AR 9 , CO 2 H and the radicals set forth in the definitions of R 2 , R 6 and R 7 ;
  • A is CH 2 , nitrogen, oxygen, sulfur or carbonyl
  • R 8 is (C 1 -C 6 )alkyl, hydrogen, phenyl or phenyl (C 1 -C 6 )alkyl;
  • R 4 is selected from oximino ( ⁇ NOH) and the radicals set forth in the definitions of R 2 , R 6 and R 7 ;
  • R 9 is a monocyclic or bicyclic heterocycle selected from the group consisting of pyrimidinyl, benzoxazolyl, 2,3-dihydro-3-oxobenzisosulfonazol-2-yl, morpholin-1-yl, thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl, isoquinolinyl, furyl, pyridyl, isothiazolyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl, thienyl, and groups of the formulae ##STR55## wherein B and D are selected from carbon, oxygen and nitrogen, and at least one of B and D is other than carbon; E is carbon or nitrogen; n is an integer from 1 to 5; any one of the carbon atoms of said (CH 2 ) n and (CH 2 ) n+1 may be optionally substituted
  • X is (CH 2 ) q wherein q is two or three and wherein one of the carbon-carbon single bonds in said (CH 2 ) q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH 2 ) q may optionally be substituted with R 6 and wherein any one of the carbon atoms of said (CH 2 ) q may optionally be substituted with R 7 ;
  • R 6 and R 7 are independently selected from hydrogen, hydroxy, halo, amino, oxo ( ⁇ O), cyano, hydroxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino, di-(C 1 -C 6 )alkylamino, C 1 -C 6 )alkoxy, ##STR56## and the radicals set forth in the definition of R 2 ; and Y is (CH 2 ) z wherein z is zero or one;
  • Preferred embodiments of this invention include methods of treating or preventing emesis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraph (69) below, that is effective in treating or preventing such condition.
  • R 1 is phenyl substituted with from one to three substituents independently selected from (C 1 -C 6 )alkyl optionally substituted with from one to three fluorine atoms and (C 1 -C 6 )alkoxy optionally substituted with from one to three flourine atoms.
  • halo as used herein, unless otherwise indicated, includes chloro, fluoro, bromo and iodo.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
  • alkenyl refers to straight or branched hydrocarbon chain radicals having one double bond including, but not limited to, ethenyl, 1- and 2-propenyl, 2-methyl-1-propenyl, 1- and 2-butenyl.
  • alkoxy refers to --O-alkyl, wherein alkyl is defined as above, and includes, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy.
  • alkylthio refers to --S-alkyl, wherein alkyl is defined as above, and includes, but is not limited to methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, and t-butylthio.
  • cycloalkyl refers to cyclic hydrocarbon radicals including, but not limited to cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • one or more substituents includes from one to the maximum number of substituents possible based on the number of available bonding sites.
  • Emesis includes the treatment of nausea, retching and vomiting.
  • Emesis includes acute emesis, delayed emesis and anticipatory emesis.
  • Substance P receptor antagonists are useful in the treatment of emesis, however induced.
  • emesis may be induced by drugs such as cancer chemotherapeutic agents (e.g., cyclophosphamide, carmustine, lomustine and chlorambucil), cytotoxic antibiotics (e.g., dactinomycin, doxorubicin, mitomycin-C and bleomycin), opioid analgesics (e.g., morphine), anti-metabolites (e.g., cytarabine, methotrexate and 5-fluorouracil), vinca alkaloids (e.g., etoposide, vinblastine and vincristine), and other drugs such as cisplatin, dacarbazine, procarbazine and hydroxyurea.
  • drugs such as cancer chemotherapeutic agents (e.g., cyclophosphamide, carmustine, lomustine and chlorambucil), cytotoxic antibiotics (e.g., dactinomycin, doxorubicin, mitomycin
  • Emesis may also be induced by radiation sickness, radiation therapy, poisons, toxins such as those caused by metabolic disorders or by infection (e.g., gastritis), pregnancy, vestibular disorders such as motion sickness, post-operative sickness, gastrointestinal obstruction, reduced gastrointestinal motility, visceral pain (e.g., myocardial infarction or peritonitis), migraine, increased intracranial pressure or decreased intracranial pressure (e.g., altitude sickness).
  • toxins such as those caused by metabolic disorders or by infection (e.g., gastritis), pregnancy, vestibular disorders such as motion sickness, post-operative sickness, gastrointestinal obstruction, reduced gastrointestinal motility, visceral pain (e.g., myocardial infarction or peritonitis), migraine, increased intracranial pressure or decreased intracranial pressure (e.g., altitude sickness).
  • the methods of this invention may also be used to treat or prevent emesis induced by the drug ipecac.
  • R 3 is a group of the formula II
  • the starting materials of the formula NH 2 R 3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic and Id may be prepared as described in U.S. Pat. No. 5,162,339, which issued on Nov. 11, 1992. This patent is incorporated herein by reference in its entirety.
  • R 3 is a group of the formula III
  • the starting materials of the formula NH R 2 R 3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic and Id may be prepared as described in PCT Patent Application PCT/US 91/02853, which designates the U.S., was filed in the United States Receiving Office on Apr. 25, 1991 and was published as WO 91/18899 on Dec.12, 1991. This application is incorporated herein by reference in its entirety.
  • R 3 is a group of the formula IV, V or VI
  • the starting materials of the formula NH 2 R 3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic and Id may be prepared as described in PCT Patent Application PCT/US 91/03369, which designates the United States, was filed on in the United States Receiving Office May 14, 1991 and was published as WO 92/01688 on Feb. 6, 1992. This application is incorporated herein by reference in its entirety.
  • R 3 is a group of the formula VII
  • the starting materials of the formula NH 2 R 3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic and Id may be prepared as described in U.S. patent application Ser. No. 724,268, filed Jul. 1, 1991, U.S. patent application Ser. No. 800,667, filed Nov. 27, 1991 and PCT Patent Application PCT/US 92/00065, which designates the United States, was filed in the United States Receiving Office on Jan. 14, 1992 and was published as WO 92/17449 on Oct. 15, 1992. These applications are incorporated herein by reference in their entirety.
  • R 3 is a group of the formula IX
  • the starting materials of the formula NH 2 R 3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic and Id may be prepared as described in U.S. patent application Ser. No. 719,884, filed Jun. 21, 1991 and PCT Patent Application PCT/US 92/04697, which designates the United States and was filed in the United States Receiving Office on Jun. 11, 1992. These applications are incorporated herein by reference in their entirety.
  • the starting materials of the formula (i) may be prepared by the procedures described in PCT Patent Application PCT/US 92/04002, which was published as WO 92/15585 on Sep. 17, 1992. This application is incorporated herein by reference in its entirety.
  • Such methods include an activated ester method that employs an acid chloride or mixed acid anhydride, and a condensation method that employs an appropriate condensing agent selected from dicyclohexylcarbodiimide (DCC), water soluble carbodiimide, 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, Bop agent, diethylcyanophosphonic acid and diphenylphospolylazide.
  • DCC dicyclohexylcarbodiimide
  • Bop agent diethylcyanophosphonic acid and diphenylphospolylazide
  • N-hydroxysuccinimide, N-hydroxybenzotriazole or 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine may be employed to prevent racemization.
  • a compound of the formula (ii) can be prepared from a compound of the formula (i) and an amino acid or its salt, which is protected by an amino group or a mono- or dialkyl substituted amino group, by the use of a peptide coupling reagent such as DCC or diethylcyanophosphonic acid in a reaction inert solvent such as methylene chloride, THF or DMF, in the presence of triethylamine.
  • a peptide coupling reagent such as DCC or diethylcyanophosphonic acid
  • a reaction inert solvent such as methylene chloride, THF or DMF
  • the resulting compound of the formula (ii) may be converted into a compound of the formula (iii) by reductive amination.
  • This route involves direct introduction of the appropriate benzylamino group at the 3-position of the quinuclidine, and is typically conducted in two steps.
  • the imine formation from the compound of formula (ii) and the benzylamine is carried out by heating the reactants at the reflux temperature in a reaction inert solvent such as toluene or benzene, in the presence of catalytic amount of acid (e.g., p-toluenesulfonate or camphorsulfonic acid (CSA)) under dehydrolytic conditions.
  • a reaction inert solvent such as toluene or benzene
  • catalytic amount of acid e.g., p-toluenesulfonate or camphorsulfonic acid (CSA)
  • a Lewis acid such as aluminum chloride or titanium tetrachloride can be used as the acid catalyst.
  • a Lewis acid such as aluminum chloride or titanium tetrachloride
  • a dehydrating agent such as molecular sieves.
  • the imine is reduced to afford the compound of the formula (iii).
  • This reduction can be carried out by either catalytic hydrogenation, or by reaction with a suitable hydride reagent such as a borohydride, borane or aluminum hydride.
  • a suitable hydride reagent such as a borohydride, borane or aluminum hydride.
  • a reagent such as NaBH 4 , NaBH 3 CN or NaBH(OAc) 3 in the presence of acetic acid is used.
  • reaction is preferably carried out using NaBH 3 CN in methanol in the presence of acetic acid.
  • the compound of the formula (iii) can be converted into the corresponding carboxylic of formula (iv) acid by acidic hydrolysis in an inorganic acid such as hydrochloric acid at a temperature from about room temperature to about the reflux temperature for about 30 minutes to several hours.
  • an inorganic acid such as hydrochloric acid
  • the resulting carboxylic acid can be converted to the corresponding ester by heating it in an alcoholic solvent in the presence of an acid catalyst.
  • the compound of formula (iii) can be prepared by the procedure illustrated in Scheme 2.
  • the compound of formula (iii) can be prepared by peptide condensation from a compound of the formula (iv) and an amino acid which is protected at its carboxyl moiety.
  • the generic synthetic condition for various peptide synthetic methods described in the above discussion of Scheme 1 can be used in this reaction.
  • the starting material of formula (v) can be obtained by debenzylation of the compound of formula (iii).
  • the debenzylation is preferably accomplished by hydrogenolysis with a palladium catalyst (e.g., palladium or palladium hydroxide) which scarcely affects the other functional groups in the compound of formula (v).
  • a palladium catalyst e.g., palladium or palladium hydroxide
  • the compounds of formula (iii) prepared by the above methods can be isolated and purified by conventional procedures, such as recrystallization or chromatography.
  • the compounds of the formulae Ia, Ib, Ic, Id, X, XI, XII, XIII, XIV, XV and XVI are useful as substance P receptor antagonists, i.e., they possess the ability to antagonize the effects of tachykinins at the substance P receptor site in mammals, and therefore they are able to function as therapeutic agents in the treatment and prevention of emesis in an afflicted mammal.
  • the therapeutic agents that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids.
  • acids that form suitable pharmaceutically acceptable salts for use in this invention are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
  • salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a therapeutic agent from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base therapeutic agents of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
  • Those therapeutic agents of this invention that are also acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • the chemical bases that are used as reagents to prepare the pharmaceutically acceptable base salts of the therapeutic agents are those that form non-toxic base salts with the acidic therapeutic agents.
  • Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
  • the therapeutic agents and their pharmaceutically acceptable salts exhibit substance P receptor-binding activity and therefore are of value in the treatment and prevention of emesis in mammals, including humans.
  • the therapeutic agents and the pharmaceutically acceptable salts thereof can be administered via either the oral, topical, rectal or parenteral routes.
  • these compounds are most desirably administered in dosages ranging from about 5.0 mg up to about 1500 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen.
  • a dosage level that is in the range of about 0.07 mg to about 21 mg per kg of body weight per day is most desirably employed. Variations may nevertheless occur depending upon the species of animal being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
  • the therapeutic agents and their pharmaceutically acceptable salts may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the routes previously indicated, and such administration may be carried out in single or multiple doses.
  • the novel therapeutic agents of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, suppositories, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • the therapeutic compounds of this invention are present in such dosage forms at concentration levels ranging from about 50% to about 70% by weight.
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions of a therapeutic agent in either sesame or peanut oil or in aqueous propylene glycol may be employed.
  • the aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic.
  • These aqueous solutions are suitable for intravenous injection purposes.
  • the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • the activity of the therapeutic agents as substance P receptor antagonists may be determined by their ability to inhibit the binding of substance P at its receptor sites in bovine caudate tissue, employing radioactive ligands to visualize the tachykinin receptors by means of autoradiography.
  • the substance P antagonizing activity of the herein described compounds may be evaluated by using the standard assay procedure described by M. A. Cascieri et al., as reported in the Journal of Biological Chemistry, Vol. 258, p. 5158 (1983). This method essentially involves determining the concentration of the individual compound required to reduce by 50% the amount of radiolabelled substance P ligands at their receptor sites in said isolated cow tissues, thereby affording characteristic IC 50 values for each compound tested.
  • bovine caudate tissue is removed from a -70° C. freezer and homogenized in 50 volumes (w./v.) of an ice-cold 50 mM Tris (i.e., trimethamine which is 2-amino-2-hydroxymethyl-1,3-propanediol)hydrochloride buffer having a pH of 7.7.
  • Tris i.e., trimethamine which is 2-amino-2-hydroxymethyl-1,3-propanediol
  • the homogenate is centrifuged at 30,000 ⁇ G for a period of 20 minutes.
  • the pellet is resuspended in 50 volumes of Tris buffer, rehomogenized and then recentrifuged at 30,000 ⁇ G for another twenty-minute period.
  • the pellet is then resuspended in 40 volumes of ice-cold 50 mM Tris buffer (pH 7.7) containing 2 mM of calcium chloride, 2 mM of magnesium chloride, 4 ⁇ g/ml of bacitracin, 4 ⁇ g/ml of leupeptin, 2 ⁇ g of chymostatin and 200 g/ml of bovine serum albumin. This step completes the production of the tissue preparation.
  • the radioligand binding procedure is then carried out in the following manner, viz., by initiating the reaction via the addition of 100 ⁇ l of the test compound made up to a concentration of 1 ⁇ M, followed by the addition of 100 ⁇ l of radioactive ligand made up to a final concentration 0.5 mM and then finally by the addition of 800 ⁇ l of the tissue preparation produced as described above.
  • the final volume is thus 1.0 ml, and the reaction mixture is next vortexed and incubated at room temperature (ca. 20° C.) for a period of 20 minutes.
  • the tubes are then filtered using a cell harvester, and the glass fiber filters (Whatman GF/B) are washed four times with 50 mM of Tris buffer (pH 7.7), with the filters having previously been presoaked for a period of two hours prior to the filtering procedure. Radioactivity is then determined in a Beta counter at 53% counting efficiency, and the IC 50 values are calculated by using standard statistical methods.
  • the glass fiber filters (Whatman GF/B) are washed four times with 50 mM of Tris buffer (pH 7.7), with the filters having previously been presoaked for a period of two hours prior to the filtering procedure. Radioactivity is then determined in a Beta counter at 53% counting efficiency, and the IC 50 values are calculated by using standard statistical methods.
  • Plasma extravasation is induced by intradermal administration of substance P (50 ⁇ l, 0.01% BSA-saline solution) in dorsal skin of pentobarbital (25 mg/kg i.p.) anesthetized male Hartley guinea pigs weighing 450-500 g.
  • the compound to be tested is dissolved in 0.1% methyl cellulose-water (MC) and dosed p.o. 1 hour before substance P challenge (3 pmol/site).
  • Evans blue dye (30 mg/kg) is administered intravenously 5 minutes before challenge. After 10 minutes, the animals are sacrificed, the dorsal skin is removed, and the blue spots are punched out using a cork borer (11.5 mm oral dose (o.d.)). Tissue dye content is quantitated after overnight formamide extraction at 600 nm absorbance.
  • Plasma extravasation is induced by intraperitoneal injection of capsaicin (10 ml of 30 ⁇ M solution in 0.1% BSA/saline) into pentobarbital anesthetized (25 mg/kg i.p.) guinea pigs.
  • capsaicin 10 ml of 30 ⁇ M solution in 0.1% BSA/saline
  • pentobarbital anesthetized 25 mg/kg i.p.
  • guinea pigs The compound to be tested is dissolved in 0.1% MC and dosed p.o. 1 hour before capsaicin challenge.
  • Evans blue dye (30 mg/kg) is administered i.v. 5 minutes before challenge. After 10 minutes, the animals are sacrificed, and both right and left ureters are removed. Tissue dye content is quantitated as in "a" above.
  • mice Male ddY mice (SLC, Japan), weighing 14-18 g, were fasted overnight.
  • the compound to be tested is dissolved in 0.1% MC and dosed p.o. 0.5 hour before acetic acid (AA) injection (0.7%, 0.16 ml/10 g body weight).
  • AA acetic acid
  • the animals are placed in clear beakers (1 per beaker) and the stretching response is counted 10 to 20 minutes after the AA injection (10 minute interval).
  • the anti-emetic activity of compounds that are substance P receptor antagonists may be determined by evaluating their ability to reduce the percentage of ferrets exhibiting emesis in response to cisplatinum exposure (10 mg/kg, i.p.).
  • the compound (2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.21]octan-3-amine inhibited cisplatinum induced emesis in ferrets when administered at a dose of 1 mg/kg s.c. (subcutaneously), 30 minutes before cisplatinum exposure.
  • the compound (2S,3S)-3-(2-methoxy-5-trifluoromethyoxybenzyl)-amino-2-phenylpiperidine inhibited cisplatinum induced emesis in ferrets when administered at a dose of 1 mg/kg s.c., 30 minutes before cisplatinum exposure.
  • the compound cis-3-[(2-methoxyphenyl)methylamino]-2-benzhydrylquinuclidine inhibited cisplatinum induced emesis in ferrets when administered at a dose of 10 mg/kg s.c., 30 minutes before cisplatinum exposure.

Abstract

The present invention relates to a method of treating or preventing emesis in mammals, including humans, using certain quinuclidine derivatives, piperidine derivatives, azanorbornane derivatives and related compounds.

Description

BACKGROUND OF THE INVENTION
The present invention relates to a method of treating or preventing emesis in mammals, including humans, using certain quinuclidine derivatives, piperidine derivatives, azanorbornane derivatives, ethylene diamine derivatives and related compounds. The pharmaceutically active compounds employed in this invention are substance P receptor antagonists.
The following references refer, collectively, to quinuclidine, piperidine, and azanorbornane derivatives and related compounds that exhibit activity as substance P receptor antagonists: U.S. Pat. No 5,162,339, which issued on Nov. 11, 1992; U.S. patent application Ser. No. 724,268, filed Jul. 1, 1991; PCT Patent Application PCT/US 91/02853, filed Apr. 25, 1991; PCT Patent Application PCT/US 91/03369, filed May 14, 1991; PCT Patent Application PCT/US 91/05776, filed Aug. 20, 1991; PCT Patent Application PCT/US 92/00113, filed Jan. 17, 1992; PCT Patent Application PCT/US 92/03571, filed May 5, 1992; PCT Patent Application PCT/US 92/03317, filed Apr. 28, 1992; PCT Patent Application PCT/US 92/04697, filed Jun. 11, 1992; U.S. patent application Ser. No. 766,488, filed Sep. 26, 1991; U.S. patent application Ser. No. 790,934, filed Nov. 12, 1991; PCT Patent Application PCT/US 92/04002, filed May 19, 1992; Japanese Patent Application 065337/92, filed Mar. 23, 1992; U.S. patent application Ser. No. 932,392, filed Aug. 19, 1992; and U.S. patent application Ser. No. 988,653, filed Dec. 10, 1992; and U.S. patent application Ser. No. 026328, filed Mar. 4, 1993.
European Patent Application 533280A1, published Mar. 24,1993, refers to the use of substance P antagonists in the treatment of emesis.
SUMMARY OF THE INVENTION
This invention relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound that is a substance P receptor antagonist, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such condition.
This invention also relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula ##STR1## wherein A is a ring system selected from phenyl, naphthyl, thienyl, quinolinyl and indolinyl, and wherein the sidechain containing NR2 R3 is attached to a carbon atom of ring system A;
AA is an aryl group selected from phenyl, naphthyl, thienyl, dihydroquinolinyl and indolinyl, and wherein the sidechain containing NR2 R3 is attached to a carbon atom of AA;
W1 is hydrogen, halo or (C1 -C6) alkyl, S--(C1 -C3)alkyl, halo or (C1 -C6) alkoxy optionally substituted with from one to three fluorine atoms.
W is hydrogen, (C1 -C6)alkyl optionally substituted with from one to three fluorine atoms, --S(O)v --(C1 -C6) alkyl wherein v is zero, one or two, halo or (C1 -C6)alkoxy optionally substituted with from one to three fluorine atoms;
R is a 4, 5 or 6 membered heterocyclic ring containing from one to three heteroatoms selected from oxygen, nitrogen and sulfur (e.g., thiazolyl, azetidinyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isothiazolyl, imidazolyl, isoxazolyl, or oxazolyl) wherein said heterocyclic ring may contain from zero to three double bonds and may optionally be substituted with one or more substituents, preferably one or two substituents, independently selected from (C1 -C6) alkyl optionally substituted with from one to three fluorine atoms and C1 -C6) alkoxy optionally substituted with from one to three fluorine atoms;
R1 is selected from amino, (C1 -C6)alkylamino, di-(C1 -C6)alkylamino, --S(O)v --(C1 -C10 )-alkyl wherein v is zero, one or two, --S(O)v -aryl wherein v is zero, one or two, --O-aryl, --SO2 NR4 R5 wherein each of R4 and R5 is, independently, (C1 -C6)alkyl, or R4 and R5, together with the nitrogen to which they are attached, form a saturated ring containing one nitrogen and from 3 to 6 carbons, ##STR2## wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, --N(SO2 --(C1 -C10)alkyl)2 and ##STR3## and wherein the aryl moieties of said --S(O)v -aryl, --O-aryl and ##STR4## are independently selected from phenyl and benzyl and may optionally be substituted with from one to three substituents independently selected from (C1 -C4)alkyl, (C1 -C4) alkoxy and halo;
or R1 is a group having the formula ##STR5## wherein a is 0, 1 or 2 and the asterisk represents a position meta to the R2 R3 NCH2 side chain;
the dotted lines in formula Ib represent that one of the X--Y and Y--Z bonds may optionally be a double bond;
X is selected from ═CH--, --CH2 --, --O--, --S--, --SO--, --SO2 --, --N(R4)--, --NH--, ═N--, --CH[(C1 -C6)alkyl]--, ═C[(C1 -C6)alkyl]--, --CH(C6 H5)-- and ═C(C6 H5)--;
Y is selected from C═O, C═NR4, C═S, ═CH--, --CH2 --, ═C[(C1 -C5)alkyl]--, --CH[(C1 -C6)alkyl]--, ═C(C6 H5)--, --CH (C6 H5)--, ═N--, --NH--, --N(R4)--, ═C(halo)--, ═C(OR4)--, ═C(SR4)--, ═C(NR4)--, --O--, --S--and SO2, wherein the phenyl moieties of said ═C(C6 H5)-- and --CH(C6 H5)-- may optionally be substituted with from one to three substituents independently selected from trifluoromethyl and halo, and wherein the alkyl moieties of said ═[(C1 -C6)alkyl]-- and --CH[C1 -C6)alkyl]-- may optionally be substituted with from one to three fluorine atoms;
Z is selected from ═CH--, --CH2 --, ═N--, --NH--, --S--, --N(R4)--, ═C(C6 H5)--, --CH(C6 H5)--, ═C[(C1 -C6)alkyl]-- and --CH[(C1 -C6)alkyl]--;
or X, Y and Z, together with the two carbon atoms shared between the benzo ring and the XYZ ring, form a fused pyridine or pyrimidine ring;
wherein X1 is hydrogen, (C1 -C10) alkoxy optionally substituted with from one to three flourine atoms or (C1 -C10) alkyl optionally substituted with from one to three fluorine atoms;
X2 and X3 are independently selected from hydrogen, halo, nitro, (C1 -C10) alkyl optionally substituted with from one to three fluorine atoms, (C1 -C10) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, hydroxy, phenyl, cyano, amino, (C1 -C6)-alkylamino, di-(C1 -C6)alkylamino, ##STR6## hydroxy(C1 -C4)alkyl, (C1 -C4)alkoxy(C1 -C4)alkyl, ##STR7## R4 is (C1 -C6) alkyl or phenyl; R2 is hydrogen or --CO2 (C1 -C10) alkyl;
R3 is selected from ##STR8## wherein R6 and R10 are independently selected from furyl, thienyl, pyridyl, indolyl, biphenyl and phenyl, wherein said phenyl may optionally be substituted with one or two substituents independently selected from halo, (C1 -C10) alkyl optionally substituted with from one to three fluorine atoms, (C1 -C10) alkoxy optionally substituted with from one to three fluorine atoms, carboxy, benzyloxycarbonyl and (C1 -C3) alkoxy-carbonyl;
R7 is selected from (C3 -C4) branched alkyl, (C5 -C6) branched alkenyl, (C5 -C7) cycloalkyl, and the radicals named in the definition of R6 ;
R8 is hydrogen or (C1 -C6) alkyl;
R9 and R19 are independently selected from phenyl, biphenyl, naphthyl, pyridyl, benzhydryl, thienyl and furyl, and R9 and R19 may optionally be substituted with from one to three substituents independently selected from halo, (C1 -C10) alkyl optionally substituted with from one to three fluorine atoms and (C1 -C10) alkoxy optionally substituted with from one to three fluorine atoms;
Y1 is (CH2)1 wherein 1 is an integer from one to three, or Y1 is a group of the formula ##STR9## Z1 is oxygen, sulfur, amino, (C1 -C6)alkylamino or (CH2)n wherein n is zero, one or two;
x is an integer from zero to four;
y is an integer from zero to four;
z is an integer from one to six, wherein the ring containing (CH2)z may contain from zero to three double bonds, and one of the carbons of (CH2)z may optionally be replaced by oxygen, sulfur or nitrogen;
o is two or three;
p is zero or one;
r is one, two or three;
R11 is thienyl, biphenyl or phenyl optionally substituted with one or two substituents independently selected from halo, (C1 -C10) alkyl optionally substituted with from one to three fluorine atoms and (C1 -C10) alkoxy optionally substituted with from one to three fluorine atoms;
X4 is (CH2)q wherein q is an integer from 1 to 6, and wherein any one of the carbon-carbon single bonds in said (CH2)q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R14, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R15 ;
m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH2)m, chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m, may optionally be substituted with R17 ;
R12 is a radical selected from hydrogen, (C1 -C6) straight or branched alkyl, (C3 -C7)cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C2 -C6)alkyl, benzhydryl and benzyl, wherein the point of attachment on R12 is a carbon atom unless R12 is hydrogen, and wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C2 -C6)alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1 -C10)alkyl optionally substituted with from one to three fluorine atoms, (C1 -C10)alkoxy optionally substituted with from one to three fluorine atoms, amino, hydroxy-(C1 -C6)alkyl, (C1 -C6)alkoxy-(C1 -C6)alkyl, (C1 -C6)-alkylamino, ##STR10## and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R13 is hydrogen, phenyl or (C1 -C6)alkyl;
or R12 and R13, together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms that is neither the point of attachment of the spiro ring nor adjacent to it may optionally be replaced by oxygen, nitrogen or sulfur;
R14 and R15 are each independently selected from hydrogen, hydroxy, halo, amino, oxo (═O), cyano, hydroxy-(C1 -C6)alkyl, (C1 -C6)alkoxy-(C1 -C6)alkyl, (C1 -C6)alkylamino, ##STR11## and the radicals set forth in the definition of R12 ; R16 is ##STR12## NHCH2 R18, SO2 R18, GR20 CO2 H or one of the radicals set forth in any of the definitions of R12, R14 and R15 ; R17 is oximino (═NOH) or one of the radicals set forth in any of the definitions of R12, R14 and R 15 ; and
R18 is (C1 -C6)alkyl, hydrogen, phenyl or phenyl (C1 -C6)alkyl;
G is selected from the group consisting of CH2, nitrogen, oxygen, sulfur and carbonyl;
R20 is a monocyclic or bicyclic heterocycle selected from the group consisting of pyrimidinyl, benzoxazolyl, 2,3-dihydro-3-oxobenzisosulfonazol-2-yl, morpholin-1-yl, thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl, isoquinolinyl, furyl, pyridyl, isothiazolyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl, thienyl, and groups of the formulae ##STR13## wherein B and D are selected from carbon, oxygen, and nitrogen, and at least one of B and D is other than carbon; E is carbon or nitrogen; n is an integer from 1 to 5; and any one of the carbons of the (CH2)n or (CH2)n+1 may be optionally substituted with (C1 -C6)alkyl or (C2 -C6) spiroalkyl, and either any two of the carbon atoms of said (CH2)n and (CH2)n+1 may be bridged by a one or two carbon atom linkage, or any one pair of adjacent carbons of said (CH2)n and (CH2)n+1 may form, together with from one to three carbon atoms that are not members of the carbonyl containing ring, a (C3 -C5) fused carbocyclic ring;
with the proviso that (a) when m is 0, one of R16 and R17 is absent and the other is hydrogen, (b) when R3 is a group of the formula VIII, R14 and R15 cannot be attached to the same carbon atom, (c) when R14 and R15 are attached to the same carbon atom, then either each of R14 and R15 is independently selected from hydrogen, fluoro, (C1 -C6)alkyl, hydroxy-(C1 -C6)alkyl and (C1 -C6)alkoxy-(C1 -C6)alkyl, or R14 and R15, together with the carbon to which they are attached, form a (C3 -C6) saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; (d) R12 and R13 cannot both be hydrogen; (e) when R14 or R15 is attached to a carbon atom of X4 or (CH2)y that is adjacent to the ring nitrogen, then R.sup. 14 or R15, respectively, must be a substituent wherein the point of attachment is a carbon atom; and (f) neither R14, R15, R16 nor R17 can form a ring with R13 ;
or a pharmaceutically acceptable salt thereof, effective in treating or preventing such condition.
The fused bicyclic nucleus of compounds of the formula Ib to which W and the --CN2 NR2 R3 sidechain are attached may be, but is not limited to one of the following groups: benzoxazolyl, benzthiazolyl, benzimidazolyl, benzisoxazolyl, benzoisothiazolyl, indazolyl, indolyl, isoquinolinyl, benzofuryl, benzothienyl, oxindolyl, benzoxazolinonyl, benzthiazolinonyl, benzimidazolinonyl, benzimidazoliniminyl, dihydrobenzothienyl-S,S-dioxide, benztriazolyl, benzthiadiazolyl, benzoxadiazolyl, and quinazolinyl.
Preferred embodiments of this invention include methods of treating or preventing emesis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (1) through (46)
below, that is effective in treating or preventing such condition.
(1) A compound of the formula Ia or Ib wherein the substituents at positions "2" and "3" of the nitrogen containing ring of R3 are in a cis configuration. (When R3 is a group of the formula VII or VIII, "a cis configuration", as used herein, means that the non-hydrogen substituent at position "3" is cis to R2).
(2) A compound of the formula Ia wherein R3 is a group of the formula III, VII or IX; R2 is hydrogen; A is phenyl or indolinyl; W is (C1 -C3)alkoxy optionally substituted with from one to five fluorine atoms; and R is thiazolyl, imidazolyl, thiadiazolyl, pyrrolyl or oxazolyl, and R may optionally be substituted with one or two (C1 -C3) alkyl moieties.
(3) A compound of the formula Ib wherein R3 is a group of the formula III, VII or IX; R2 is hydrogen; the fused bicyclic ring system to which W and the --CH2 NR2 R3 sidechain are attached is benzoxazolyl, benzisoxazolyl, benzthiazolyl or benzimidazolyl; and W is (C1 -C6)alkoxy optionally substituted with from one to five fluorine atoms.
(4) A compound as defined in paragraph 1, 2 or 3 above wherein: (a) R3 is a group of the formula III and R9 is benzhydryl; (b) R3 is a group of the formula VII, R12 is phenyl, each of R13, R14, R15 and R16 is hydrogen, m is zero and X4 is --(CH2)3 --; or (c) R3 is a group of the formula IX, r is two and R19 is benzhydryl.
(5) A compound of the formula Ia wherein: (a) R3 is a group of the formula III wherein the substituents at positions "2" and "3" of the nitrogen containing ring are in the cis configuration, R9 is benzhydryl and A is phenyl; or (b) R3 is a group of the formula VII wherein R12 and the substituent at position "3" of the nitrogen containing ring are in the cis configuration, A is phenyl, R12 is phenyl each of R2, R13, R14, R15 and R16 is hydrogen, m is zero, W is methoxy or isopropoxy, X4 is --(CH2)3 -- and R is thiazolyl, imidazolyl, pyrrolyl, oxazolyl or thiadiazolyl.
(6) A compound of the formula Ib wherein R3 is a group of the formula IX wherein the substituents at positions "2" and "3" of the nitrogen containing ring are in the cis configuration, R19 is benzhydryl, r is two and the fused bicyclic ring system to which W and the --CH2 NR2 R3 sidechain are attached is benzisoxazolyl or benzthiazolyl.
(7) A compound of the formula Ib wherein R3 is a group of the formula IX, R19 is benzhydryl the fused bicyclic ring system to which W and the --CH2 NR2 R3 sidechain are attached is benzisoxazolyl, and W is methoxy.
(8) A compound of the formula Ib wherein R3 is a group of the formula VII, R12 is phenyl, each of R13, R14, R15 and R16 is hydrogen, m is zero, X4 is --(CH2)3 --, and the fused bicyclic ring system to which W and the --CH2 NR2 R3 sidechain are attached is benzothiazolyl, benzoxazolyl or benzimidazolyl.
(9) A compound of the formula Ia wherein R3 is a group of the formula VII, each of R13, R14, R15 and R16 is hydrogen, m is zero, X4 is --(CH2)3 --, A is phenyl, W is methoxy, and R is selected from thiazolyl, imidazolyl, thiadiazolyl and isoxazolyl.
(10) A compound of the formula Ia or Ib that is selected from:
(2S,3S)-3-[2-methoxy-5-(2-thiazolyl)benzyl]amino-2-phenylpiperidine;
(2S,3S)-3-[5-(2-imidazolyl)-2-methoxybenzyl]amino-2-phenylpiperidine;
(2S,3S)-3-[2-methoxy-5-(2-oxopyrrolidinyl)benzyl]amino-2-phenylpiperidine;
(2S,3S)-3-[2-methoxy-5-(4-methyl-2-thiazolyl)benzyl]amino-2-phenylpiperidine;
(2S,3S)-3-[2-methoxy-5-(1,2,3-thiadiazol-4-yl)benzyl]amino-2-phenylpiperidine;
(2S,3S)-(6-methoxy-2-methyl-benzothiazol-5-ylmethyl)(2-phenylpiperidin-3-yl)amine;
(2S,3S )-[5-(2,5-dimethyl-pyrrol-1-yl)-2-methoxybenzyl]-(2-phenylpiperidin-3-yl)amine;
(2S,3S )-3-[2-methoxy-5-(5-oxazolyl)benzyl]amino-2-phenylpiperidine;
(2S,3S )-(6-methoxy-2-methyl-benzoxazol-5-ylmethyl)-(2-phenyl-piperidin-3-yl)-amine; and
(1SR,2SR,3SR,4RS)-3-[6-methoxy-3-methylbenzisoxazol-5yl]methylamino-2-benzhydrylazanorbornane.
(11) A compound of the formula Ic, wherein R3 is a group of the formula II, III, VII or IX; R2 is hydrogen; ring AA is phenyl or indolinyl; W1 is (C1 -C3)alkoxy optionally substituted with from one to three fluorine atoms; and R1 is S(O)v --(C1 -C10)alkyl wherein v is zero, one or two, S(O)v -aryl wherein v is zero, one or two, --O---aryl, ##STR14## wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, --N(SO2 --(C1 -C10)alkyl)2 or ##STR15## wherein said aryl is phenyl or benzyl and may optionally be substituted with from one to three substituents independently selected from (C1 -C6)alkyl, (C1 -C4)alkoxy and halo.
(12) A compound as defined in paragraph 11 above, wherein R3 is a group of the formula II, o is two, and each R6 and R7 is phenyl.
(13) A compound as defined in paragraph 11 above, wherein R3 is a group of the formula VII, each of R13, R14, R15 and R16 is hydrogen, R12 is phenyl, m is zero and X4 is --(CH2)3 --.
(14) A compound as defined in paragraph 11 above, wherein R3 is a group of the formula IX, R19 is benzhydryl and r is two.
(15) A compound as defined in paragraph 11 above, wherein R3 is a group of the formula III, R8 is other than hydrogen and R9 is benzyhydryl.
(16) A compound to the formula Ic wherein the substituents at positions "2" and "3" of the nitrogen containing ring are in the cis configuration.
(17) A compound of the formula 1c wherein R3 is a group of the formula II wherein the substituents at positions "2" and "3" of the nitrogen containing ring are in the cis configuration, o is two, each of R6 and R7 is phenyl and ring AA is phenyl or indolinyl.
(18) A compound of the formula Ic wherein R3 is a group of the formula III wherein the substituents at positions "2" and "3" of the nitrogen containing ring are in the cis configuration, R8 is other than hydrogen, R9 is benzhydryl and ring AA is phenyl.
(19) A compound of the formula Ic wherein R3 is a group of the formula VII wherein R12 and the substituent at position "3" of the nitrogen containing ring are in the cis configuration, ring AA is phenyl, R12 is phenyl, each of R2, R13, R14, R15 and R16 is hydrogen, m is zero X4 is --(CH2)2 -- or --(CH2)3 -- and R1 is selected from S(O)v --(C1 -C10) alkyl wherein v is zero one or two and ##STR16## and di-(C1 -C6) alkylamino.
(20) A compound as defined in paragraph 19 above, wherein X4 is --(CH2)2 -- and W1 is (C1 -C6) alkoxy optionally substituted with from one to three fluorine atoms.
(21) A compound as defined in paragraph 19 above, wherein X4 is --(CH2)3 -- and W1 is (C1 -C6) alkoxy optionally substituted with from one to three fluorine atoms.
(22) A compound of the formula Ic, wherein R3 is a group of the formula IX wherein the substituents at positions "2" and "3" of the nitrogen containing ring are in the cis configuration, r is two and R19 is benzhydryl.
(23) A compound as defined in paragraph 22 above, wherein ring AA is phenyl, W1 is (C1 -C5) alkoxy optionally substituted with from one to three fluorine atoms and R1 is selected from --S(O)v --(C1 -C10)alkyl wherein v is zero, one or two, di-(C1 -C6)alkylamino and ##STR17##
(24) A compound as defined in paragraph 15 above, wherein ring AA is phenyl, Wl is (C1 -C6)alkoxy optionally substituted with from one to three fluorine atoms, and R1 is selected from --S(O)v --(C1 -C10)alkyl wherein v is zero, one or two, and ##STR18##
(25) A compound as defined in paragraph 15 above, wherein ring AA is phenyl, W1 is (C1 -C6)alkoxy optionally substituted with from one to three fluorine atoms, and R1 is selected from amino, (C1 -C6)alkylamino or di-(C1 -C6)alkylamino.
(26) A compound as defined in paragraph 12 above, wherein ring AA is phenyl, W1 is (C1 -C6)alkoxy optionally substituted with from one to three fluorine atoms, and R1 is selected from --S(O)v --(C1 -C10)alkyl wherein v is zero, one or two, and ##STR19##
(27) A compound as defined in paragraph 12 above, wherein ring AA is phenyl, W1 is (C1 -C6)alkoxy optionally substituted with from one to three fluorine atoms, and R1 is selected from amino, (C1 -C6)alkylamino or di-(C1 -C6)alkylamino.
(28) A compound as defined in paragraph 24 above, wherein W1 is attached at the "2" position of ring AA and R1 is attached at the "5" position of ring AA, relative to the point of attachment of the NR2 R3 containing side chain.
(29) A compound as defined in paragraph 25 above, wherein W1 is attached at the "2" position of ring AA and R1 is attached at the "5" position of ring AA, relative to the point of attachment of the NR2 R3 containing side chain.
(30) A compound as defined in paragraph 26 above, wherein W1 is attached at the "2" position of ring AA and R1 is attached at the "5" position of ring AA, relative to the point of attachment of the NR2 R2 containing side chain.
(31) A compound as defined in paragraph 27 above, wherein W1 is attached at the "2" position of ring AA and R1 is attached at the "5" position of ring AA, relative to the point of attachment of the NR2 R3 containing side chain.
(32 ) A compound as defined in paragraph 13 above, wherein ring AA is phenyl, W1 is selected from isopropoxy, OCF3, OCH3, OCHF2 and OCH2 CF3, and R1 is selected from --S(O)v -- (C1 -C10)alkyl wherein v is zero, one or two, and (C1 -C10)alkyl-N-SO2 --(C1 -C10)alkyl.
(33) A compound selected from the group consisting of:
(2S,3S )-N-(2 -methoxy-5-methylsulfonylphenyl)-methyl-2-diphenylmethyl-1-azabicyclo [2.2.2 ]octan-3-amine;
(2S,3S )-N-(2-methoxy-5-methylthiophenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S )-N-(2-methoxy-5-dimethylaminophenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine; and
(2S,3S)-N-(5-trifluoroacetylamino-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3 -amine.
(34) A compound of the formula Ic, wherein R3 is a group of the formula VII, m is zero, each of R13, R15, R16 and R17 is hydrogen, R12 is phenyl, R14 is ##STR20## ring AA is phenyl, W1 is (C1 -C3) alkoxy and R1 is selected from (C1 -C15)alkyl, --SCH3, SO2 CH3, SOCH3, (C1 -C6)alkylamino and di-(C1 -C6)alkyl-amino.
(35 ) A compound of the formula Ic, having the formula ##STR21##
(36) A compound of the formula Id wherein R6, R10, R11 and R13 are phenyl, R8 is hydrogen, R9 is phenyl optionally substituted with chlorine, fluorine, (C1 -C6) alkyl optionally substituted with from one to three fluorine atoms or (C1 -C6) alkoxy optionally substituted with from one to three fluorine atoms, m is 0 and n is 3 or 4.
(37) A compound of the formula Id that is selected from the group consisting of:
(2S,3S)-3-(5-tert-butyl-2-methoxybenzyl)amino-2-(3-trifluoromethoxyphenyl)piperidine;
(2S,3S)-3-(2-isopropoxy-5-trifluoromethoxybenzyl)amino-2-phenyl-piperidine;
(2S,3S)-3-(2-ethoxy-5-trifluoromethoxybenzyl)amino-2-phenyl-piperidine;
(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine;
(2S,3S)-3(-5-tert-butyl-2-trifluoromethoxybenzyl)amino-2-phenylpiperidine;
2-(diphenylmethyl)-N-(2-methoxy-5-trifluoromethoxy-phenyl)methyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)benzyl]amino-2-phenylpiperidine;
(2S,3S)-3-(5-tert-butyl-2-trifluoromethoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(2-isopropoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine;
(2S,3S )-3 -(2-difluoromethoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-2-phenyl-3-[2-(2,2,2-trifluoroethoxybenzyl)aminopiperidine; and
(2S,3S )-2-phenyl-3-(2-trifluoromethoxybenzyl)]aminopiperidine.
(38) A compound of the formula Id, wherein R3 is a group of the formula II wherein o is two or three and each of R6 and R7 is phenyl or substituted phenyl.
(39) A compound of the formula Id, wherein R3 is a group of the formula III, R8 is hydrogen and R9 is phenyl or substituted phenyl.
(40) A compound of the formula Id, wherein R3 is a group of the formula IV wherein 1 is one or two and each of R10 and R11 is phenyl or substituted phenyl.
(41) A compound of the formula Id, wherein R3 is a group of the formula V wherein n is zero or one and each of R10 and R11 is phenyl or substituted phenyl.
(42) A compound of the formula Id, wherein R3 is a group of the formula VI wherein p is one and each of R10 and R11 are phenyl or substituted phenyl.
(43) A compound of the formula Id, wherein R3 is a group of the formula VII wherein q is two, three or four, m is zero and R12 is phenyl or substituted phenyl.
(44) A compound of the formula Id, wherein R3 is a group of the formula VIII wherein y is zero, x is zero or one, z is three or four, m is zero and R12 is phenyl or substituted phenyl.
(45) A compound of the formula Id wherein R3 is a group of the formula VII, R6, R14, R13, R16 and R15 are hydrogen, R12 is phenyl, X1 is 2-methoxy, X2 and X3 are independently selected from hydrogen, chlorine, fluorine, methyl, (C1 -C6)alkoxy and trifluoromethane, m is 0 and q is 3 or 4.
(46) A compound of the formula Id wherein R3 is a group of the formula VII and said compound is selected from the group consisting of:
cis-3-(2-chlorobenzylamino)-2-phenylpiperidine;
cis-3-(2-trifluoromethylbenzylamino)-2-phenylpiperidine;
cis-3-(2-methoxybenzylamino)-2-(2-fluorophenyl)piperidine;
cis-3-(2-methoxybenzylamino)-2-(2-chlorophenyl)piperidine;
cis-3-(2-methoxybenzylamino)-2-(2-methylphenyl)piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-methoxyphenyl)piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-fluorophenyl)piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-chlorophenyl)piperidine;
cis-3-(2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(2-methoxybenzylamino)-2-(3-methylphenyl)piperidine;
cis-3-(2-methoxybenzylamino)-2-(4-fluorophenyl)piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-thienyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-phenylazacyclo-heptane;
3-(2-methoxybenzylamino)-4-methyl-2-phenyl-piperidine;
3-(2-methoxybenzylamino)-5-methyl-2-phenyl-piperidine;
3-(2-methoxybenzylamino)-6-methyl-2-phenyl-piperidine;
(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(5-carboethoxypent-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(6-hydroxy-hex1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(4-hydroxy-4-phenylbut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(4-oxo-4-phenylbut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(5,6-dihydroxyhex1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(5-fluoro-2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-[4-(4-fluorophenyl)-4-oxobut-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-[4-[4-fluorophenyl)-4-hydroxybut-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(2-methoxy-5-methylbenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(4-benzamidobut-1-yl)-3-(2-methoxybenzyl-amino)-2-phenylpiperidine;
cis-3-(2-methoxynaphth-1-ylmethylamino)-2-phenylpiperidine;
(2S,3S)-3-(2-methoxybenzylamino)-1-(5-N-methylcarboxamidopent-1-yl)-2-phenylpiperidine;
(2S,3S)-1-(4-cyanobut-1-yl)-3-(2-methoxybenzylamino)-2phenylpiperidine;
(2S,3S)-1-[4-(2-naphthamido)but-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidin
(2S,3S)-1-(5-benzamidopent-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(5-aminopent-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-3-(5-chloro-2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-3-(2,5-dimethoxybenzylamino)-2-phenylpiperidine;
cis-3-(3,5-difluoro-2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(4,5-difluoro-2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(2,5-dimethoxybenzylamino)-1-[4-(4-fluorophenyl)-4-oxobut-1-yl]-2-phenylpiperidine;
cis-3-(5-chloro-2-methoxybenzylamino)-1-(5,6-dihydroxyhex-1-yl)-2-phenylpiperidine;
cis-1-(5,6-dihydroxyhex1-yl)-3-(2,5-dimethoxybenzylamino)-2-phenylpiperidine;
cis-2-phenyl-3-[-2(prop-2-yloxy)benzylamino]piperidine;
cis-3-(2,5-dimethoxybenzyl)amino-2-(3-methoxyphenyl)piperidine hydrochloride;
cis-3-(5-chloro-2-methoxybenzyl)amino-2-(3-methoxyphenyl)piperidine dihydrochloride;
cis-3-(5-chloro-2-methoxybenzyl)amino-2-(3-chlorophenyl)piperidine dihydrochloride;
3-(2-methoxybenzylamino)-2,4-diphenylpiperidine;
cis-3-(2-methoxybenzylamino)-2-phenylpyrrolidine;
(2S,3S)-3-(5-ethyl-2-methoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(5-n-butyl-2-methoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(2-methoxy-5-n-propylbenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(5-isopropyl-2-methoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(5-s-butyl-2-methoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(5-t-butyl-2-methoxybenzyl)amino-2-phenylpiperidine; and
(2S,3S)-3-(2-methoxy-5-phenylbenzyl)amino-2-phenylpiperidine.
(47) A compound of the formula Id, wherein R3 is a group of the formula II or III and said compound is selected from the group consisting of:
(2S,3S)-N-(5-isopropyl-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(5-tert-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(5-methyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(5-ethyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-N-(5-sec-butyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine; and
(2S,3S)-N-(5-n-propyl-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine.
This invention also relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound having the formula ##STR22## wherein W is Y or X(CH2)n ; Y is optionally substituted (C1 -C6)alkyl, optionally substituted (C2 -C6)alkenyl or optionally substituted (C3 -C8)cycloalkyl;
X is optionally substituted (C1 -C6)alkoxy, CONR1 R2, CO2 R1, CHR1 OR2, CHR1 NR2 R3, COR1, CONR1 OR2 or optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and n is an integer from zero to six;
Ar1, Ar2 and Ar3 are each, independently, optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl;
and R1, R2 and R3 are independently selected from hydrogen, optionally substituted C1 -C6)alkyl, optionally substituted (C1 -C6)alkoxy, optionally substituted (C3 -C8)cycloalkyl, optionally substituted aryl, wherein said aryl is selected from phenyl, naphthyl, pyridyl, quinolyl, thienyl, furyl, phenoxyphenyl, oxazolyl, tetrazolyl, thiazolyl, imidazolyl and pyrazolyl; and optionally substituted (C1 -C5)heterocyclic groups, wherein said heterocyclic groups are selected from pyrrolidino, piperidino, morpholino, piperazinyl and thiamorpholino;
and wherein the substituents on the foregoing substituted alkyl, alkenyl, cycloalkyl and alkoxy groups are independently selected from halo, nitro, amino, (C1 -C4)alkyl, (C1 -C4)alkoxy, trifluoromethyl and trifluoromethoxy;
and wherein the substituents on the foregoing substituted (C1 -C5) heterocyclic groups are attached to a sulfur or nitrogen atom on the ring and are independently selected from oxygen, di-oxygen and (C1 -C4)alkyl;
and wherein the substituents on said substituted Ar1 groups are independently selected from (C1 -C6)alkyl optionally substituted with from one to three halo groups, (C1 -C6)alkoxy optionally substituted with from one to three halo groups, (C1 -C6)alkylsulfinyl, (C2 -C6)alkenyl, (C1 -C6)alkylthio, (C1 -C6)alkylsulfonyl, (C1 -C6)alkylsulfonylamino, and di-(C1 -C6)alkylamino wherein one or both of the alkyl groups may be optionally substituted with a (C1 -C6)alkylsulfonyl, or (C1 -C6)alkylsulfinyl group;
and wherein the substituents on said substituted Ar2 and Ar3 groups are independently selected from (C1 -C4)alkyl, (Cl -C4)alkoxy, (C1 -C4)alkylthio, (C1 -C4)alkylsulfinyl, di-(C1 -C4)alkylamino, trifluoromethyl and trifluoromethoxy; with the proviso that when Y is unsubstituted or is substituted with (C1 -C4)alkyl, it is attached to the 4- or 6-position of the quinuclidine ring;
or a pharmaceutically acceptable salt of such compound, effective in treating or preventing such condition.
Preferred embodiments of this invention include methods of treating or preventing emesis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (48) through (53) below, that is effective in treating or preventing such condition.
(48) A compound of the formula X, wherein W is X(CH2)n. (49) A compound of the formula X, wherein W is Y. (50) A compound of the formula X, wherein Ar1 is substituted aryl and W is Y. (51) A compound of the formula X, wherein Ar1 is mono-, di- or tri-substituted phenyl and W is Y. (52) A compound of the formula X, wherein Ar1 is phenyl disubstituted at the 2- and 5-positions and W is Y. (53) A compound of the formula X, wherein Ar1 is paramethoxyphenyl, each of Ar2 and Ar3 is phenyl and W is Y. (54) A compound of the formula X that is selected from the group consisting of:
(3R,4S,5S,6S)-N,N-diethyl-5-(5-isopropyl-2-methoxybenzylamino-6-diphenylmethyl-1-azabicyclo[2.2.21octane-3-carboxamide;
(3R,4S,5S,6S)-N,N-diethyl-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R,4S,5S,6S)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-2-methylthiobenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo-[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(5-ethyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxyl-5-n-propylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(5-sec-butyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(5-N-methyl-methanesulfonylamino-2-methoxy-benzylamino)-6-diphenylmethyl-1azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfinylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-trifluoromethoxybenzylamino-6-diphenylmethyl-1-azabicyclo[2.2.21octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfonylbenzylamino-6-diphenylmethyl-1-azabicyclo[2.2.21octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(5-dimethylamino-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.21octane-3-carboxylic acid;
(3R,4S,5S,6S)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.21octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylthiobenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.21octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2,5-dimethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.21octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.21octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(5-ethyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.21octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxyl-5-n-propylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.21octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(5-sec-butyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.21octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(5-N-methylmethanesulfonylamino-2-methoxybenzyl-amino)-6-diphenylmethyl-1-azabicyclo[2.2.21octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfinylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.21octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-trifluoromethoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.21octane-2-carboxylic acid;
(3R,4S,5S,6S)-5-(2-methoxy-5-methylsulfonylbenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.21octane-2-carboxylic acid; and
(3R,4S,5S,6S)-5-(5-dimethylamino-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.21octane-2-carboxylic acid.
This invention also relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound having the formula ##STR23## wherein R1 is selected from hydrogen, (C1 -C6) straight or branched alkyl, (C3 -C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, biphenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2 -C6) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2 -C6) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1 -C6) alkyl optionally substituted with from one to three fluorine atoms, (C1 -C6) alkoxy, amino, trihaloalkoxy (e.g., trifluoromethoxy), ##STR24## and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R3 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C3 -C7) cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, (C1 -C6) alkyl optionally substituted with from one to three fluorine atoms, (C1 -C6) alkoxy optionally substituted with from one to three fluorine atoms, amino, phenyl, trihaloalkoxy (e.g., trifluoromethoxy), ##STR25## one of R5 and R6 is hydrogen and the other is selected from hydroxyethyl, hydrogen, (C1 -C3)alkyl, (C1 -C8) acyloxy-(C1 -C3)alkyl, (C1 -C8)alkoxyethyl and benzyloxyethyl;
R7 and R8 are independently selected from hydrogen, (C1 -C3)alkyl and phenyl;
R9 is selected from methyl, hydroxyethyl, ##STR26## R14 R15 NCO2 CH2 --, R16 OCO2 CH2 --, (C1 -C4)alkyl-CO2 CH2 --, --CONR17 R18, R17 R18 NCO2 --, R19 OCO2 --, C6 H5 CH2 CO2 CH2 --, C6 H5 CO2 CH2 --, (C1 -C4)alkyl-CH(OH)--, C6 H5 CH(OH)--, C6 H5 CH2 CH(OH)--, CH2 halo, R20 SO2 OCH2, --CO2 R16 and R21 CO2 --;
R10 and R11 are independently selected from hydrogen, (C1 -C3) alkyl and phenyl;
R12 is hydrogen, benzyl or a group of the formula ##STR27## wherein m is an integer from zero to twelve, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH2)m chain, may optionally be replaced by a carbon-carbon double or triple bond, and any one of the carbon atoms of (CH2)m may optionally be substituted with R23 ;
R13, R14, R15, R16, R17, R18, R19, R20, R21 and R24 are independently selected from hydrogen, (C1 -C3)alkyl and phenyl;
R22 and R23 are independently selected from hydrogen, hydroxy, halo, amino, carboxy, carboxy(C1 -C6)alkyl, (C1 -C6)alkylamino, di-(C1 -C6)alkylamino, (C1 -6)alkoxy, ##STR28## (C1 -C6) straight or branched alkyl, (C3 -C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C2 -C6)alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C2 -C6)alkyl and benzhydryl may optionally be substituted with one or two substituents independently selected from halo, nitro, (C1 -C6)alkyl optionally substituted with from one to three fluorine atoms, (C1 -C6)alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, amino, (C1 -C6)-alkylamino, ##STR29## and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
or R9, together with the carbon to which it is attached, the nitrogen of the pyrrolidine ring, the carbon to which R7 is attached and the carbon to which R5 and R6 are attached form a second pyrrolidine ring; with the proviso that when R9 together with the carbon to which it is attached the nitrogen of the pyrrolidine ring, the carbon to which R7 is attached and the carbon to which R5 and R6 are attached, form a second pyrrolidine ring (thus forming a bicyclic structure containing a bridgehead nitrogen), either R12 is absent or R12 is present and the nitrogen of the second pyrrolidine ring is positively charged; or a pharmaceutically acceptable salt of such compound, effective in treating or preventing such condition.
Compounds of the formula XI that contain two pyrrolidine rings may be represented by one of the following two structures, depending on whether R12 is present or absent. ##STR30## Preferred embodiments of this invention include methods of treating or preventing emesis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (55) through (59) below, that is effective in treating or preventing such condition.
(55) A compound of the formula XI wherein R1 is benzhydryl.
(56) A compound of the formula XI wherein R1 is diphenylmethyl, R3 is aryl selected from phenyl or indanyl wherein each of said aryl groups may be optionally substituted with one, two or three substituents, each of R5, R6, R7, R8, R10 , and R11 is hydrogen, R9 is selected from hydroxymethyl, methoxymethyl, --CO2 R16, --CONR17 R18, R14 R15 NCO2 CH2 --, R16 OCO2 CH2 --, (C1 -C4)alkyl-CO2 CH2 --, C6 H5 CH2 CO2 CH2 --, --CH2 halo and R20 SO2 OCH2 --, and R12 is hydrogen or benzyl.
(57) A compound of the formula XI wherein Rl is phenyl, R3 is aryl selected from phenyl or indanyl wherein each of said aryl groups may be optionally substituted with one, two or three substituents, each of R5, R6, R7, R8, R10, and R11 is hydrogen, R9 is selected from hydroxymethyl, methoxymethyl, --CO2 R18, --CONR17 R18, R14 R15 NCO2 CH2 CH2 --, R16 OCO2 CH2 --, (C1 -C4)alkyl-CO2 CH2 --, --CH2 halo, R20 SO2 OCH--, and R12 is hydrogen or benzyl.
(58) A compound of the formula XI wherein R1 is diphenylmethyl, R3 is aryl selected from phenyl or indanyl wherein each of said aryl groups may be optionally substituted with one, two or three substituents, each of R5, R6, R7, R8, R10, R11 and R13 is hydrogen, and wherein R9, together with the carbon to which it is attached, the nitrogen of the pyrrolidine ring, the carbon to which R7 is attached and the carbon to which R5 and R7 are attached, form a second pyrrolidine ring (thus forming a bicyclic structure containing a bridgehead nitrogen).
(59) A compound of the formula XI that is selected from the group consisting of:
(2S,3S,4R)-2-diphenylmethyl-3-[(2-methoxy-4,5-dimethylphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR,3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-4,5-dimethylphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR,3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(methylethyl)phenyl)methylamino]-4-(carbomethoxymethyl)pyrrolidine;
(2SR,3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(methylethyl)phenyl)methylamino]-4-(carboxymethyl)pyrrolidine;
(2SR,3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(methylethyl)phenyl)methylamino]-4-(2-dimethylaminocarbamoylethyl)pyrrolidine;
(2SR,3SR,4RS)-2-diphenylmethyl-3-[(2-trifluoromethoxyphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2S,3S,4R)-2-diphenylmethyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR,3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-methoxyethyl)pyrrolidine;
(2S,3S,4R)-2-diphenylmethyl-3-[(2-methoxy-5-methylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR,3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-methylethyl)phenyl)methylamino ]-4-(2-methoxyethyl)pyrrolidine;
(2SR,3SR,4RS)-2-diphenylmethyl-3-[(2-methyl-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(1SR,2SR,3SR,4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-4,5-dimethylphenyl)-methylamino]-bicyclo[2.2.1]heptane;
(1SR,2SR,3SR,4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxyphenyl)methylamino]bicyclo[2.2.1]heptane;
(1SR,2SR,3SR,4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]bicyclo[2.2.1]heptane;
(1SR,2SR,3SR,4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-trifluoromethoxyphenyl)methylamino]bicyclo[2.2.1]heptane;
(1SR,2SR,3SR,4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-(1-methylethyl)phenyl)methylamino]bicyclo[2.2.1]heptane;
(1SR,2SR,3SR,4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-propylphenyl)methylamino ]bicyclo[2.2.1]heptane;
(1SR,2SR,3SR,4RS)-1-aza-2-diphenylmethyl-3-[(2-methoxy-5-(1-methylpropyl)phenyl)methylamino]bicyclo[2.2.1]heptane;
(1SR,2SR,3SR,4RS)-1-aza-2-phenyl-3-[(2-methoxyphenyl)methylamino]bicyclo[2.2.1]heptane;
(1SR,2SR,3RS,4RS)-1-aza-2-phenyl-3-[(2-methoxy-5-trifluoromethoxyphenyl)methylamino]bicyclo[2.2.1]heptane;
(2SR,3SR,4RS)-N-1-phenylmethyl-2-diphenylmethyl-3-[(2-methoxyphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR,3SR,4RS)-2-diphenylmethyl-3-[(2-methoxyphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR,3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR,3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-trifluoromethoxyphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR,3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(1-methylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR,3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-propylphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR,3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-(1-methyl-1-propyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR,3SR,4RS)-2-diphenylmethyl-3-[(2-trifluoromethoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2hydroxyethyl)pyrrolidine;
(2SR,3SR,4RS)-2-diphenylmethyl-3-[(2-methoxy-5-chlorophenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR,3SR,4RS)-2-phenyl-3-[(2-methoxyphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine;
(2SR,3SR,4RS)-2-phenyl-3-[(2-methoxy-5-(1,1-dimethylethyl)phenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine; and
(2SR,3SR,4RS)-2-phenyl-3-[(2-methoxy-5-trifluoromethoxyphenyl)methylamino]-4-(2-hydroxyethyl)pyrrolidine.
This invention also relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula ##STR31## wherein R1 is hydrogen, (C1 -C8) alkyl, a saturated (C6 -C10) carbocyclic ring system containing two fused rings, a saturated (C6 -C10) carbocyclic bridged ring system containing two rings, or benzyl wherein the phenyl moiety of said benzyl may optionally be substituted with one or more substituents independently selected from halo, (C1 -C6) alkyl optionally substituted with from one to three fluorine atoms and (C1 -C8) alkoxy optionally substituted with from one to three fluorine atoms;
R2 is hydrogen, benzyl or a group of the formula ##STR32## wherein m is an integer from zero to twelve, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom of the (CH2)m chain, may optionally be replaced by a carbon-carbon double or triple bond, and any one of the carbon atoms of (CH2)m may optionally be substituted with R9 ;
R8 and R9 are independently selected from hydrogen, hydroxy, halo, amino, carboxy, carboxy(C1 -C6)alkyl, (C1 -C6)alkylamino, di-(C1 -C6)alkylamino, (C1 -C6)alkoxy, ##STR33## straight or branched alkyl, (C3 -C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C2 -C6)alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C2 -C6)alkyl and benzhydryl may optionally be substituted with one or two substituents independently selected from halo, nitro, (C1 -C6)alkyl optionally substituted with from one to three fluorine atoms, (C1 -C6)alkoxy optionally substituted with from one to three fluorine atoms, ##STR34## and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
or R1 and R2, together with the nitrogen to which they are attached, form a saturated or unsaturated monocyclic ring containing from three to eight carbon atoms, a fused bicyclic ring containing from six to ten carbon atoms, or a saturated bridged ring system containing from six to ten carbon atoms;
R4 is aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having from three to seven carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C3 -C7) cycloalkyl may optionally be substituted with one, two or three substituents, each of said substituents being independently selected from halo, nitro, (C1 -C6) alkyl optionally substituted with from one to three fluorine atoms, (C1 -C6) alkoxy optionally substituted with from one to three fluorine atoms, phenyl, ##STR35## R3 is hydrogen (C3 -C8)cycloalkyl, (C1 -C6) straight or branched alkyl or phenyl optionally substituted with one or more substituents independently selected from halo, (C1 -C6)alkyl optionally substituted with from one to three fluorine atoms, and (C1 -C6) alkoxy optionally substituted with from one to three fluorine atoms;
R5 is hydrogen, (C1 -C6) alkyl, or phenyl optionally substituted with one or more substituents independently selected from halo, (C1 -C6)alkyl optionally substituted with from one to three fluorine atoms and (C1 -C6)alkoxy optionally substituted with from one to three fluorine atoms;
R6 is selected from hydrogen, (C1 -C6) straight or branched alkyl, (C3 -C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, biphenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2 -C6) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2 -C6) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1 -C6) alkyl optionally substituted with from one to three fluorine atoms, (C1 -C6) alkoxy, trifluoromethyl, amino, trihaloalkoxy ##STR36## and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl; and
R12 is hydrogen, (C1 -C3)alkyl or phenyl;
or a pharmaceutically acceptable salt of such compound, that is effective in treating or preventing such condition.
Preferred embodiments of this invention include methods of treating or preventing emesis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (60) through (62) below, that is effective in treating or preventing such condition.
(60) A compound of the formula XII wherein R2 is hydrogen or R2 and R1 together with the nitrogen to which they are attached, form a monocyclic ring containing five to seven carbon atoms; R3 is hydrogen, methyl or phenyl; R5 is hydrogen; R4 is phenyl or indanyl, wherein said phenyl or indanyl may optionally be substituted with from one to three substituents independently selected from halo, nitro, (C1 -C6) alkyl optionally substituted with from one to three fluorine atoms, (C1 -C6) alkoxy, trihaloalkoxy (e.g., trifluoromethoxy), (C1 -C6) alkylamino, --C (O)NH--(C1 -C8)alkyl, (C1 -C6)alkyl-C(O)--, --C(O)--O--(C1 -C6)alkyl, --C(O)H, --CH2 OR12, --NH(C1 -C6)alkyl, --NHC(O)H, --NHC(O)-C1 -C6)alkyl, --NHSO2 (C1 -C6)alkyl and (C1 -C6)alkyl--N--SO2 --(C1 -C6)alkyl; and R6 is phenyl.
(61) A compound of the formula XII wherein R1 is alkyl, R6 is unsubstituted phenyl, R4 is a monosubstituted or disubstituted aryl group that is substituted at the C-2 position with an alkoxy group or substituted at the C-5 position with an alkyl, alkoxy or trihaloalkoxy group, or substituted in such manner at both C-2 and C-5 positions (i.e., with an alkoxy group at the C-2 position and an alkyl, alkoxy or trihaloalkoxy group at the C-5 position), and each of R2, R3 and R5 is hydrogen.
(62) A compound of the formula XII that is selected from the group consisting of:
1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxy-5-trifluoromethoxyphenyl)methyl]-1,2-ethanediamine;
1-N-pyrrolidyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-methyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-cyclopentyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-propyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-phenylmethyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-cyclooctyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-cyclobutyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-(2-adamantyl)-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-(1,1-dimethylethyl)-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-cyclopropyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-isopropyl-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-(1-phenylethyl)-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine;
1-N-(2-norbornyl)-1-phenyl-2-N'-[(2-methoxyphenyl)methyl ]-1,2-ethanediamine;
1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxy-5-tertbutylphenyl)methyl]-1,2-ethanediamine;
1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxy-5-isopropylphenyl)methyl]-1,2-ethanediamine;
1-N-cyclohexyl-1-phenyl-2-N'-[(2-methoxy-4,5-dimethylphenyl)methyl]-1,2-ethanediamine; and
1-N-cyclohexyl-1-N-(6-hydroxyhexyl)-1-phenyl-2-N'-[(2-methoxyphenyl)methyl]-1,2-ethanediamine.
This invention also relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula ##STR37## wherein R1 is cycloalkyl having from five to seven carbon atoms, pyrrolyl, thienyl, pyridyl, phenyl or substituted phenyl, wherein said substituted phenyl is substituted with from one to three substituents independently selected from fluorine, chlorine, bromine, trifluoromethyl, alkyl having from one to three carbon atoms, alkoxy having from one to three carbon atoms, carboxy, alkoxycarbonyl having from one to three carbon atoms in the alkoxy moiety and benzyloxycarbonyl;
R2 is furyl, thienyl, pyridyl, indolyl, biphenyl, phenyl or substituted phenyl, wherein said substituted phenyl is substituted with one or two substituents independently selected from fluorine, chlorine, bromine, trifluoromethyl, alkyl having from one to three carbon atoms, alkoxy having from one to three carbon atoms, carboxy, alkoxycarbonyl having from one to three carbon atoms in the alkoxy moiety and benzyloxycarbonyl; and
R3 is thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl, or a pharmaceutically acceptable salt of such compound, effective in treating or preventing such condition.
Preferred embodiments of this invention include methods of treating or preventing emesis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (63) through (65) below, that is effective in treating or preventing such condition.
(63) A compound of the formula XIII, wherein R1 is phenyl or substituted phenyl.
(64) A compound of the formula XIII, wherein R1 is methoxyphenyl.
(65) A compound of the formula XIII, wherein said compound is (±)-cis-9-diphenylmethyl-N-((2-methoxyphenyl)methyl)-10-azatricyclo[4.4.1.05,7 ]undecan-8-amine.
This invention also relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula ##STR38## wherein m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH2)m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m may optionally be substituted with R8 ;
w is an integer from 0 to 2;
y is an integer from 1 to 4;
z is an integer from 1 to 4, and wherein any one of the carbon atoms of said (CH2)z may optionally be substituted with
R1 is hydrogen or (C1 -C8)alkyl optionally substituted with hydroxy, alkoxy or fluoro;
R2 is a group selected from hydrogen, (C1 -C6)straight or branched alkyl, (C3 -C7)cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from phenyl, indanyl, and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl(C2 -C6)alkyl, benzhydryl and benzyl, wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl and wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl(C1 -C6)alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1 -C6)alkyl, (C1 -C6)alkoxy, trifluoromethyl, amino, ##STR39## R5 is hydrogen, phenyl or (C1 -C6)alkyl; or R2 and R5, together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;
R3 is aryl selected from phenyl, indanyl, and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C3 -C7)cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, (C1 -C6)alkyl optionally substituted with from one to three fluorine atoms, (C1 -C6)alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, phenyl, amino, (C1 -C6)alkylamino, (C1 -C6)dialkyl amino, ##STR40## R4 is independently selected from hydrogen, hydroxy, halo, amino, oxo (═O), nitrile, (C1 -C6)alkylamino, di-(C1 -C6)alkylamino, C1 -C6)alkoxy, ##STR41## and the groups set forth in the definition of R2 ; R6 is ##STR42## NHCH2 R9, NHSO2 R9 or one of the groups set forth in any of the definitions of R2, and R4 ;
R8 is oximino (═NOH) or one of the groups set forth in any of the definitions of R2 and R4 ;
R9 is (C1 -C6)alkyl, hydrogen, phenyl or phenyl (C1 -C6)alkyl;
with the proviso that (a) when m is 0, R8 is absent and R6 is hydrogen, (b) neither R4, R6, nor R8 can form, together with the carbon to which it is attached, a ring with R5, (c) the sum of y and z must be less than 7; or a pharmaceutically acceptable salt thereof, effective in treating or preventing such condition.
Preferred embodiments of this invention include methods of treating or preventing emesis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraphs (66) through (68) below, that is effective in treating or preventing such condition.
(66) A compound of the formula XIV, wherein R2 is a radical selected from hydrogen, phenyl, naphthyl and benzhydryl; wherein each of said phenyl, naphthyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1 -C6) alkyl, (C1 -C6)alkoxy, trifluoromethyl, amino, ##STR43## and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl.
(67) A compound of the formula XIV, wherein R2 is a group selected from hydrogen, phenyl, naphthyl and benzhydryl; wherein each of said phenyl, naphthyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1 -C6) alkyl, (C1 -C6)alkoxy, trifluoromethyl, amino, (C1 -C6)-alkylamino, ##STR44## and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl; and
R4 is independently selected from hydrogen, hydroxy, halo, amino, oxo (═O), nitrile, (C1 -C6)alkylamino, di-(C1 -C6)alkylamino, (C1 -C6)alkoxy, ##STR45## (C1 -C6)alkyl and phenyl.
(68) A compound of the formula XIV, wherein said compound is (3RS,4RS)-3-phenyl-4-(2-methoxybenzyl)amino-2-azabicyclo[3.3.1]nonane.
This invention also relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal a compound of the formula ##STR46## wherein X1 is C1 -C5 alkoxy or halosubstituted (C1 -C5)alkoxy;
X2 is hydrogen, halogen, (C1 -C5)alkyl, (C2 -C5)alkenyl, (C2 -C5)alkynyl, (C1 -C5)alkoxy, (C1 -C6)alkylthio, (C1 -C5) alkylsulfinyl, (C1 -C5)alkylsulfonyl, halosubstituted (C1 -C5) alkyl, halosubstituted (C1 -C5)alkoxy, (C1 -C8)alkylamino, dialkylamino having from 1 to 5 carbon atoms in each alkyl moiety, (C1 -C8)alkylsulfonylamino (which may be substituted by halogen), N--(C1 -C5)alkyl-N--(C1 -C5)alkylsulfonylamino (which may be substituted by halogen in the alkylsulfonyl moiety), (C1 -C5)alkanoylamino (which may be substituted by halogen) or N--(C1 -C5)alkyl-N--(C1 -C5)alkanoylamino (which may be substituted by halogen in the alkanoyl moiety);
Ar1 and Ar2 are each, independently, thienyl, phenyl, fluorophenyl, chlorophenyl or bromophenyl;
A is Y--(CH2)m --CH(R2)--(CH2)n --NR1 --;
R1 is hydrogen, (C1 -C5)alkyl, benzyl or --(CH2)p --Y;
R2 is hydrogen, (C1 -C5)alkyl (which may be substituted by a substituent selected from the group consisting of hydroxy, amino, methylthio and mercapto), benzyl, 4-hydroxybenzyl, 3-indolylmethyl or --(CH2)p --Y;
Y is --CN, --CH2 Z or --COZ;
Z is hydroxy, amino, (C1 -C5)alkoxy, (C1 -C5)alkylamino or dialkylamino having from 1 to 5 carbon atoms in each alkyl moiety;
m, n and p are each, independently, 0, 1, 2 or 3; and
R1 and R2 may be connected to form a ring;
or a pharmaceutically acceptable salt of such compound, that is effective in treating or preventing such condition.
Preferred embodiments of this invention include methods of treating or preventing emesis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraph (69) below, that is effective in treating or preventing such condition.
(69) A compound of the formula XV, wherein said compound is selected from the group consisting of:
(3R,4S,5S,6S)-N-carbamoylmethyl-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-carboxamide;
(3R,4S,5S,6S)-N-carboxymethyl-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.21]octane-3-carboxamide;
(3R,4S,5S,6S)-3-(2-carbamoylpyrrolidin-1-yl)carbonyl-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.21]octane;
(3R*,4S*,5S*,6S*)-N-(1-carbamoylethyl)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.21]octane-3-carboxamide;
(3R,4S,5S,6S)-N-(1-carbamoyl-3-methylbutyl)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.21]octane-3-carboxamide; and
(3R,4S,5S,6S)-N-(2-carbamoylethyl)-5-(5-isopropyl-2-methoxybenzylamino)-6-diphenylmethyl-1-azabicyclo[2.2.21]octane-3-carboxamide.
This invention also relates to a method of treating or preventing emesis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula ##STR47## wherein R1 is phenyl optionally substituted with one or more substituents, preferably with from one to three substituents, independently selected from hydrogen, halo, nitro, (C1 -C10)alkyl optionally substituted with from one to three fluorine atoms, (C1 -C10)alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, hydroxy, phenyl, cyano, amino, (C1 -C6)-alkylamino, ##STR48## (C1 -C4)alkoxy (C1 -C4)alkyl, --S(O)v -- (C1 -C10)-alkyl wherein v is zero, one or two, --S (O)v -aryl wherein v is zero, one or two, --O-aryl, --SO2 NR4 R5 wherein each of R4 and R5 is, independently, (C1 -C6)alkyl, or R4 and R5, together with the nitrogen to which they are attached, form a saturated ring containing one nitrogen and from 3 to 6 carbons. ##STR49## wherein one or both of the alkyl moieties may optionally be substituted with from one to three fluorine atoms, --N(SO2 --(C1 -C10)alkyl)2 and ##STR50## and wherein the aryl moieties of said --S(O)v -aryl, --O-aryl and ##STR51## are independently selected from phenyl and benzyl and may optionally be substituted with from one to three substituents independently selected from (C1 -C4)alkyl, (C1 -C4)alkoxy and halo;
or R1 is phenyl substituted with a group having the formula ##STR52## wherein a is 0, 1 or 2 and the asterisk represents a position meta to the point of attachment of R1 ;
R2 is selected from (C1 -C6) straight or branched alkyl, (C3 -C7)cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl (C2 -C6)alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2 -C6)alkyl and benzhydryl may optionally be substituted with one or more substituents, preferably with from one to three substituents, independently selected from halo, nitro, (C1 -C10)alkyl optionally substituted with from one to three fluorine atoms, (C1 -C10)alkoxy optionally substituted with from one to three fluorine atoms, amino, hydroxy-(C1 -C6)alkyl, (C1 -C6)alkoxy-(C1 -C6)alkyl, (C1 -C6)-alkylamino, ##STR53## and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom in the (CH2)m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m, may optionally be substituted with R4 ;
R3 is selected from ##STR54## NHCH2 R8, SO2 R8, AR9, CO2 H and the radicals set forth in the definitions of R2, R6 and R7 ;
A is CH2, nitrogen, oxygen, sulfur or carbonyl;
R8 is (C1 -C6)alkyl, hydrogen, phenyl or phenyl (C1 -C6)alkyl;
R4 is selected from oximino (═NOH) and the radicals set forth in the definitions of R2, R6 and R7 ;
R9 is a monocyclic or bicyclic heterocycle selected from the group consisting of pyrimidinyl, benzoxazolyl, 2,3-dihydro-3-oxobenzisosulfonazol-2-yl, morpholin-1-yl, thiomorpholin-1-yl, benzofuranyl, benzothienyl, indolyl, isoindolyl, isoquinolinyl, furyl, pyridyl, isothiazolyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl, thienyl, and groups of the formulae ##STR55## wherein B and D are selected from carbon, oxygen and nitrogen, and at least one of B and D is other than carbon; E is carbon or nitrogen; n is an integer from 1 to 5; any one of the carbon atoms of said (CH2)n and (CH2)n+1 may be optionally substituted with (C1 -C6)alkyl or (C2 -C6) spiroalkyl; and either any one pair of the carbon atoms of said (CH2)n and (CH2)n+1 may be bridged by a one or two carbon atom linkage, or any one pair of adjacent carbon atoms of said (CH2)n and (CH2)n+1 may form, together with from one to three carbon atoms that are not members of the carbonyl containing ring, a (C3 -C5) fused carbocyclic ring;
X is (CH2)q wherein q is two or three and wherein one of the carbon-carbon single bonds in said (CH2)q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R6 and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R7 ;
R6 and R7 are independently selected from hydrogen, hydroxy, halo, amino, oxo (═O), cyano, hydroxy-(C1 -C6)alkyl, (C1 -C6)alkoxy-(C1 -C6)alkyl, (C1 -C6)alkylamino, di-(C1 -C6)alkylamino, C1 -C6)alkoxy, ##STR56## and the radicals set forth in the definition of R2 ; and Y is (CH2)z wherein z is zero or one;
with the proviso that: (a) when A is --(CH2)-- or carbonyl, R9 cannot be furyl, pyridyl, isothiazolyl, oxazolyl, triazolyl, tetrazolyl, quinolyl, thiazolyl or thienyl; (b) when m is zero, one of R3 and R4 is absent and the other is hydrogen; and (c) when R6 or R7 is attached to a carbon atom of X that is adjacent to the ring nitrogen, then R6 or R7 respectively, must be a substituent wherein the point of attachment is a carbon atom;
or a pharmaceutically acceptable salt of such compound, that is effective in treating or preventing such condition.
Preferred embodiments of this invention include methods of treating or preventing emesis in a mammal, including a human, that comprise administering to said mammal an amount of a compound as defined in paragraph (69) below, that is effective in treating or preventing such condition.
(70) A compound of the formula XVI wherein z is one.
(71) A compound of the formula XVI wherein q is three.
(72) A compound of the formula XVI wherein q is three, m is zero, R3 is hydrogen and R4 is absent.
(73) A compound of the formula XVI wherein R1 is phenyl substituted with from one to three substituents independently selected from (C1 -C6)alkyl optionally substituted with from one to three fluorine atoms and (C1 -C6)alkoxy optionally substituted with from one to three flourine atoms.
(74) A compound of the formula XVI wherein z is one, m is zero, R4 is absent, and each of R3, R6 and R7 is hydrogen.
(75) A compound of the formula XVI that is selected from the group consisting of:
(±)-[3R-[3α,6α(R*)]]-3-phenyl-7-phenyl-1,8-diazaspiro[5.5]undecane; and
(±)-[3R-[3α,6α(R*)]]-3-(2-methoxyphenyl)-7-phenyl-1,8-diazaspiro [5.5]undecane.
Other compounds of the formula I include the following:
(±)-[3R-[3α,6α(R*)]]-3-(2-methoxy-5-trifluoromethoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(±)-[3R-[3α,6α(R*)]]-3-(5-chloro-2-methoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(±)-[3R-[3α,6α(R*)]]-3-(5-isopropyl-2-methoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(±)-[3R-[3α,6α(R*)]]-3-(5-tert.butyl-2-methoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(±)-[3R-[3α,6α(R*)]]-3-(2-methoxy-5-(N-methyl-N-methylsulfonylaminophenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(±)-[3R-[3α,6α(R*)]]-3-(2-iodophenyl)-7-phenyl-8,8-diazaspiro[5.5]undecane;
(±)-[3R-[3α,6α(R*)]]-3-(2-methoxy-4-methylphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(±)-[3R-[3α,6α(R*)]]-3-(2-isopropoxyphenyl)-7-phenyl-1,8-diazaspiro[5.5]undecane;
(±)-[3R-[3α,6α(R*)]]-3-(2-difluoromethoxy-5-trifluoromethoxyphenyl)-7-phenyl-1,8diazaspiro [5.5]undecane;
(±)-[3R-[3α,5α(R*)]]-3-(2-methoxyphenyl)-6-phenyl1,7-diazaspiro[4.5]decane;
(±)-[3R-[3α,5α(R*)]]-3-(2-methoxy-5-trifluoromethoxyphenyl)-6-phenyl-1,7-diazaspiro[4.5]decane;
(±)-[3R-[3α,5α(R*)]]-3-(5-chloro-2-methoxyphenyl)-6-phenyl-1,7-diazaspiro[4.5]decane;
(±)-[3R-[3α,5α(R*)]]-3-(5-isopropyl-2-methoxyphenyl)-6-phenyl-1,7-diazaspiro[4.5]decane; and
(±)-[3R-[3α,5α(R*)]]-3-(5-tert.butyl-2-methoxyphenyl)-6-phenyl-1,7-diazaspiro[4.5]decane.
The term "halo", as used herein, unless otherwise indicated, includes chloro, fluoro, bromo and iodo.
The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term "alkenyl", as used herein, unless otherwise indicated, refers to straight or branched hydrocarbon chain radicals having one double bond including, but not limited to, ethenyl, 1- and 2-propenyl, 2-methyl-1-propenyl, 1- and 2-butenyl.
The term "alkoxy", as used herein, unless otherwise indicated, refers to --O-alkyl, wherein alkyl is defined as above, and includes, but is not limited to methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and t-butoxy.
The term "alkylthio", as used herein, unless otherwise indicated, refers to --S-alkyl, wherein alkyl is defined as above, and includes, but is not limited to methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, and t-butylthio.
The term "cycloalkyl", as used herein, unless otherwise indicated, refers to cyclic hydrocarbon radicals including, but not limited to cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "one or more substituents," as used herein, includes from one to the maximum number of substituents possible based on the number of available bonding sites.
Compounds of the formulae I, X, XI, XII, XIII, XIV, XV and XVI contain chiral centers and therefore exist in different enantiomeric forms. The above definitions of these compounds include all optical isomers and all stereoisomers of such compounds, and mixtures thereof.
The treatment of emesis includes the treatment of nausea, retching and vomiting. Emesis includes acute emesis, delayed emesis and anticipatory emesis. Substance P receptor antagonists are useful in the treatment of emesis, however induced. For example, emesis may be induced by drugs such as cancer chemotherapeutic agents (e.g., cyclophosphamide, carmustine, lomustine and chlorambucil), cytotoxic antibiotics (e.g., dactinomycin, doxorubicin, mitomycin-C and bleomycin), opioid analgesics (e.g., morphine), anti-metabolites (e.g., cytarabine, methotrexate and 5-fluorouracil), vinca alkaloids (e.g., etoposide, vinblastine and vincristine), and other drugs such as cisplatin, dacarbazine, procarbazine and hydroxyurea. Emesis may also be induced by radiation sickness, radiation therapy, poisons, toxins such as those caused by metabolic disorders or by infection (e.g., gastritis), pregnancy, vestibular disorders such as motion sickness, post-operative sickness, gastrointestinal obstruction, reduced gastrointestinal motility, visceral pain (e.g., myocardial infarction or peritonitis), migraine, increased intracranial pressure or decreased intracranial pressure (e.g., altitude sickness).
The methods of this invention may also be used to treat or prevent emesis induced by the drug ipecac.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the formulae Ia, Ib, Ic, Id, X, XI, XII, XIII, and XIV may be prepared as described below. Unless otherwise indicated, in the discussion that follows, structural formulae Ia, Ib, Ic, Id, X, XI XII, XIII, and XIV, and groups II, III, IV, V, VI, VII, VIII and IX are defined as above.
Compounds of the formula Ia and Ib may be prepared as described in U.S. patent application Ser No. 988,653, which was filed on Dec. 10, 1992. This application is incorporated herein by reference in its entirety.
Compounds of the formula Ic may be prepared as described in U.S. patent Application Ser. No. 932,392, which was filed on Aug. 19, 1992. This application is incorporated herein by reference in its entirety.
Compounds of the formula Id may be prepared as described in PCT Patent Application PCT/US 92/03571, which designates the United States was filed in the United States Receiving Office on May 5, 1992 as a continuation-in part of abandoned U.S. Ser. No. 717,943 (filed Jun. 20, 1991) and was published on Jan. 7, 1993 as WO 93/00331. This application is incorporated herein by reference in its entirety.
When R3 is a group of the formula II, the starting materials of the formula NH2 R3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic and Id may be prepared as described in U.S. Pat. No. 5,162,339, which issued on Nov. 11, 1992. This patent is incorporated herein by reference in its entirety.
When R3 is a group of the formula III, the starting materials of the formula NH R2 R3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic and Id may be prepared as described in PCT Patent Application PCT/US 91/02853, which designates the U.S., was filed in the United States Receiving Office on Apr. 25, 1991 and was published as WO 91/18899 on Dec.12, 1991. This application is incorporated herein by reference in its entirety.
When R3 is a group of the formula IV, V or VI, the starting materials of the formula NH2 R3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic and Id may be prepared as described in PCT Patent Application PCT/US 91/03369, which designates the United States, was filed on in the United States Receiving Office May 14, 1991 and was published as WO 92/01688 on Feb. 6, 1992. This application is incorporated herein by reference in its entirety.
When R3 is a group of the formula VII, the starting materials of the formula NH2 R3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic and Id may be prepared as described in U.S. patent application Ser. No. 724,268, filed Jul. 1, 1991, U.S. patent application Ser. No. 800,667, filed Nov. 27, 1991 and PCT Patent Application PCT/US 92/00065, which designates the United States, was filed in the United States Receiving Office on Jan. 14, 1992 and was published as WO 92/17449 on Oct. 15, 1992. These applications are incorporated herein by reference in their entirety.
When R3 is a group of the formula VIII, the starting materials of the formula NH2 R3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic and Id may be prepared as described in PCT Patent Application PCT/US 91/05776, which designates the United States, was filed in the United States Receiving Office on Aug. 20, 1991 and was published as WO 92/06079 on Apr. 16, 1992, U.S. patent application Ser. No. 800,667, filed Nov. 27, 1991 and PCT Patent Application PCT/US 92/00065, which designates the United States, was filed in the United States Receiving Office on Jan. 14, 1992 and was published as WO 92/17449 on Oct. 15, 1992. These applications are incorporated herein by reference in their entirety.
When R3 is a group of the formula IX, the starting materials of the formula NH2 R3 that are used in the preparation of compounds of the formulae Ia, Ib, Ic and Id may be prepared as described in U.S. patent application Ser. No. 719,884, filed Jun. 21, 1991 and PCT Patent Application PCT/US 92/04697, which designates the United States and was filed in the United States Receiving Office on Jun. 11, 1992. These applications are incorporated herein by reference in their entirety.
Compounds of the formula X may be prepared as described in PCT Patent Application PCT/US 92/04002, which designates the United States, was filed in the United States Receiving Office on May 19, 1992 and was published as WO 92/15585 on Sep. 17, 1992. This application is incorporated herein by reference in its entirety.
Compounds of the formula XI may be prepared as described in PCT Patent Application PCT/US 92/04697, which designates the United States, was filed in the United States Receiving Office on Jun. 11, 1992. This application is incorporated herein by reference in its entirety.
Compounds of the formula XII may be prepared as described in PCT Patent Application PCT/US 92/07730, which designates the United States and was filed in the United States Receiving Office on Sep. 18, 1992. This application is incorporated herein by reference in its entirety.
Compounds of the formula XIII may be prepared as described in PCT Patent Application PCT/US 92/06819, which designates the United States and was filed in the United States Receiving Office on Aug. 20, 1992. This application is incorporated herein by reference in its entirety.
Compounds of the formula XIV may be prepared as described in U.S. patent application Ser. No. 885,110, which was filed on May 18, 1992. This application is incorporated herein by reference in its entirety.
Compounds of the formula XV may be prepared by the procedure described in Japanese Patent Application 065337/92, which was filed on Mar. 23, 1992. These procedures are depicted in Schemes 1, 2 and 3 and discussed below. In the reaction schemes and discussion that follow, A, X1, X2, Ar1 and Ar2 are defined as in the definition of compounds of the formula XV above. ##STR57##
Referring to Scheme 1, the starting materials of the formula (i) may be prepared by the procedures described in PCT Patent Application PCT/US 92/04002, which was published as WO 92/15585 on Sep. 17, 1992. This application is incorporated herein by reference in its entirety.
Introduction of a protected amino acid into a compound of the formula (i) to give a compound of the formula (ii) can be carried out by a variety of conventional methods for peptide synthesis, as described in "Peptide synthesis, the basis and experiments", edited by N Izumiya, 1985 (Maruzen).
Such methods include an activated ester method that employs an acid chloride or mixed acid anhydride, and a condensation method that employs an appropriate condensing agent selected from dicyclohexylcarbodiimide (DCC), water soluble carbodiimide, 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, Bop agent, diethylcyanophosphonic acid and diphenylphospolylazide.
If necessary, addition of a tertiary amide such as triethylamine can promote the condensation reaction. N-hydroxysuccinimide, N-hydroxybenzotriazole or 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine may be employed to prevent racemization.
Typically, a compound of the formula (ii) can be prepared from a compound of the formula (i) and an amino acid or its salt, which is protected by an amino group or a mono- or dialkyl substituted amino group, by the use of a peptide coupling reagent such as DCC or diethylcyanophosphonic acid in a reaction inert solvent such as methylene chloride, THF or DMF, in the presence of triethylamine.
The resulting compound of the formula (ii) may be converted into a compound of the formula (iii) by reductive amination. This route involves direct introduction of the appropriate benzylamino group at the 3-position of the quinuclidine, and is typically conducted in two steps. In the first step, the imine formation from the compound of formula (ii) and the benzylamine is carried out by heating the reactants at the reflux temperature in a reaction inert solvent such as toluene or benzene, in the presence of catalytic amount of acid (e.g., p-toluenesulfonate or camphorsulfonic acid (CSA)) under dehydrolytic conditions. Alternatively, a Lewis acid such as aluminum chloride or titanium tetrachloride can be used as the acid catalyst. Under such catalytic conditions, and at temperatures from about -78° C. to about room temperature, it is preferable to use an acetonitrile or methylene chloride solvent together with a dehydrating agent such as molecular sieves.
In the second step, the imine is reduced to afford the compound of the formula (iii). This reduction can be carried out by either catalytic hydrogenation, or by reaction with a suitable hydride reagent such as a borohydride, borane or aluminum hydride. Typically, a reagent such as NaBH4, NaBH3 CN or NaBH(OAc)3 in the presence of acetic acid is used.
The above two reaction steps can be carried out simultaneously. In such cases, the reaction is preferably carried out using NaBH3 CN in methanol in the presence of acetic acid.
The compound of the formula (iii) can be converted into the corresponding carboxylic of formula (iv) acid by acidic hydrolysis in an inorganic acid such as hydrochloric acid at a temperature from about room temperature to about the reflux temperature for about 30 minutes to several hours.
The resulting carboxylic acid can be converted to the corresponding ester by heating it in an alcoholic solvent in the presence of an acid catalyst.
Alternatively, the compound of formula (iii) can be prepared by the procedure illustrated in Scheme 2. Referring to Scheme 2, the compound of formula (iii) can be prepared by peptide condensation from a compound of the formula (iv) and an amino acid which is protected at its carboxyl moiety. The generic synthetic condition for various peptide synthetic methods described in the above discussion of Scheme 1 can be used in this reaction.
The procedure illustrated in Scheme 3 can also be used to prepare compounds of the formula (iii). Using this procedure, compounds of the formula (iii) can be prepared by reductive amination of 3-amino quinuclidines of the formula (v) having an amino acid as the substituent A with the corresponding substituted benzaldehyde. This reductive amination reaction proceeds easily under standard reaction conditions because it goes by way of a stable imine intermediate. Use of a borane reducing agent (e.g. NaBH3 CN or NaBH(Oac)3 etc.) is preferred.
The starting material of formula (v) can be obtained by debenzylation of the compound of formula (iii). The debenzylation is preferably accomplished by hydrogenolysis with a palladium catalyst (e.g., palladium or palladium hydroxide) which scarcely affects the other functional groups in the compound of formula (v).
The compounds of formula (iii) prepared by the above methods can be isolated and purified by conventional procedures, such as recrystallization or chromatography.
Compounds of the formula XVI may be prepared as described in U.S. patent application Ser. No. 026,382, which was filed on Apr. 7, 1993. This application is incorporated herein by reference in its entirety.
The compounds of the formulae Ia, Ib, Ic, Id, X, XI, XII, XIII, XIV, XV and XVI (hereinafter referred to, collectively, as the "therapeutic agents") and the pharmaceutically acceptable salts thereof are useful as substance P receptor antagonists, i.e., they possess the ability to antagonize the effects of tachykinins at the substance P receptor site in mammals, and therefore they are able to function as therapeutic agents in the treatment and prevention of emesis in an afflicted mammal.
The therapeutic agents that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Examples of acids that form suitable pharmaceutically acceptable salts for use in this invention are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a therapeutic agent from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base therapeutic agents of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
Those therapeutic agents of this invention that are also acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. The chemical bases that are used as reagents to prepare the pharmaceutically acceptable base salts of the therapeutic agents are those that form non-toxic base salts with the acidic therapeutic agents. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
The therapeutic agents and their pharmaceutically acceptable salts exhibit substance P receptor-binding activity and therefore are of value in the treatment and prevention of emesis in mammals, including humans.
The therapeutic agents and the pharmaceutically acceptable salts thereof can be administered via either the oral, topical, rectal or parenteral routes. In general, these compounds are most desirably administered in dosages ranging from about 5.0 mg up to about 1500 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 0.07 mg to about 21 mg per kg of body weight per day is most desirably employed. Variations may nevertheless occur depending upon the species of animal being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
The therapeutic agents and their pharmaceutically acceptable salts may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the novel therapeutic agents of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, suppositories, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutic compounds of this invention are present in such dosage forms at concentration levels ranging from about 50% to about 70% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of a therapeutic agent in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
The activity of the therapeutic agents as substance P receptor antagonists may be determined by their ability to inhibit the binding of substance P at its receptor sites in bovine caudate tissue, employing radioactive ligands to visualize the tachykinin receptors by means of autoradiography. The substance P antagonizing activity of the herein described compounds may be evaluated by using the standard assay procedure described by M. A. Cascieri et al., as reported in the Journal of Biological Chemistry, Vol. 258, p. 5158 (1983). This method essentially involves determining the concentration of the individual compound required to reduce by 50% the amount of radiolabelled substance P ligands at their receptor sites in said isolated cow tissues, thereby affording characteristic IC50 values for each compound tested.
In this procedure, bovine caudate tissue is removed from a -70° C. freezer and homogenized in 50 volumes (w./v.) of an ice-cold 50 mM Tris (i.e., trimethamine which is 2-amino-2-hydroxymethyl-1,3-propanediol)hydrochloride buffer having a pH of 7.7. The homogenate is centrifuged at 30,000 ×G for a period of 20 minutes. The pellet is resuspended in 50 volumes of Tris buffer, rehomogenized and then recentrifuged at 30,000 ×G for another twenty-minute period. The pellet is then resuspended in 40 volumes of ice-cold 50 mM Tris buffer (pH 7.7) containing 2 mM of calcium chloride, 2 mM of magnesium chloride, 4 μg/ml of bacitracin, 4 μg/ml of leupeptin, 2 μg of chymostatin and 200 g/ml of bovine serum albumin. This step completes the production of the tissue preparation.
The radioligand binding procedure is then carried out in the following manner, viz., by initiating the reaction via the addition of 100 μl of the test compound made up to a concentration of 1 μM, followed by the addition of 100 μl of radioactive ligand made up to a final concentration 0.5 mM and then finally by the addition of 800 μl of the tissue preparation produced as described above. The final volume is thus 1.0 ml, and the reaction mixture is next vortexed and incubated at room temperature (ca. 20° C.) for a period of 20 minutes. The tubes are then filtered using a cell harvester, and the glass fiber filters (Whatman GF/B) are washed four times with 50 mM of Tris buffer (pH 7.7), with the filters having previously been presoaked for a period of two hours prior to the filtering procedure. Radioactivity is then determined in a Beta counter at 53% counting efficiency, and the IC50 values are calculated by using standard statistical methods.
The ability of the therapeutic agents to inhibit substance P induced effects in vivo may be determined by the following procedures "a" through "c". (Procedures "a" through "c" are described in Nagahisa et al., European Journal of Pharmacology, 217, 191-5 (1992), which is incorporated herein by reference in its entirety.)
a. Plasma extravasation in the skin
Plasma extravasation is induced by intradermal administration of substance P (50 μl, 0.01% BSA-saline solution) in dorsal skin of pentobarbital (25 mg/kg i.p.) anesthetized male Hartley guinea pigs weighing 450-500 g. The compound to be tested is dissolved in 0.1% methyl cellulose-water (MC) and dosed p.o. 1 hour before substance P challenge (3 pmol/site). Evans blue dye (30 mg/kg) is administered intravenously 5 minutes before challenge. After 10 minutes, the animals are sacrificed, the dorsal skin is removed, and the blue spots are punched out using a cork borer (11.5 mm oral dose (o.d.)). Tissue dye content is quantitated after overnight formamide extraction at 600 nm absorbance.
b. Capsaicin-induced plasma extravasation
Plasma extravasation is induced by intraperitoneal injection of capsaicin (10 ml of 30 μM solution in 0.1% BSA/saline) into pentobarbital anesthetized (25 mg/kg i.p.) guinea pigs. The compound to be tested is dissolved in 0.1% MC and dosed p.o. 1 hour before capsaicin challenge. Evans blue dye (30 mg/kg) is administered i.v. 5 minutes before challenge. After 10 minutes, the animals are sacrificed, and both right and left ureters are removed. Tissue dye content is quantitated as in "a" above.
c. Acetic acid-induced abdominal stretching
Male ddY mice (SLC, Japan), weighing 14-18 g, were fasted overnight. The compound to be tested is dissolved in 0.1% MC and dosed p.o. 0.5 hour before acetic acid (AA) injection (0.7%, 0.16 ml/10 g body weight). The animals are placed in clear beakers (1 per beaker) and the stretching response is counted 10 to 20 minutes after the AA injection (10 minute interval).
The anti-emetic activity of compounds that are substance P receptor antagonists may be determined by evaluating their ability to reduce the percentage of ferrets exhibiting emesis in response to cisplatinum exposure (10 mg/kg, i.p.). The compound (2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.21]octan-3-amine inhibited cisplatinum induced emesis in ferrets when administered at a dose of 1 mg/kg s.c. (subcutaneously), 30 minutes before cisplatinum exposure. The compound (2S,3S)-3-(2-methoxy-5-trifluoromethyoxybenzyl)-amino-2-phenylpiperidine inhibited cisplatinum induced emesis in ferrets when administered at a dose of 1 mg/kg s.c., 30 minutes before cisplatinum exposure. The compound cis-3-[(2-methoxyphenyl)methylamino]-2-benzhydrylquinuclidine inhibited cisplatinum induced emesis in ferrets when administered at a dose of 10 mg/kg s.c., 30 minutes before cisplatinum exposure.

Claims (3)

We claim:
1. A method of treating or preventing emesis in a mammal, comprising administering to said mammal an amount of a compound of the formula ##STR58## wherein X1 is hydrogen, (C1 -C10)alkoxy optionally substituted with from one to three fluorine atoms or (C1 -C10) alkyl optionally substituted with from one to three fluorine atoms;
X2 and X3 are independently selected from hydrogen, halo, nitro, (C1 -C10)alkyl optionally substituted with from one to three fluorine atoms, (C1 -C10)alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl hydroxy, phenyl, cyano, amino, (C1 -C6)-alkylamino, di-(C1 -C6)alkylamino, ##STR59## hydroxy(C1 -C6)alkyl, (C1 -C4)alkoxy(C1 -C4)alkyl, ##STR60## and R3 is a group of the formula ##STR61## wherein X4 is (CH2)q wherein q is an integer from 2 to 4; m is O;
R16 is hydrogen;
R17 is absent;
R12 is a radical selected from hydrogen, (C1 -C6) straight or branched alkyl, (C3 -C7)cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C2 -C6)alkyl, benzhydryl and benzyl, wherein the point of attachment on R12 is a carbon atom unless R12 is hydrogen, and wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C2 -C6)alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1 -C10)alkyl optionally substituted with from one to three fluorine atoms, (C1 -C10)alkoxy optionally substituted with from one to three fluorine atoms, amino, hydroxy-(C1 -C6)alkyl, (C1 -C6)alkoxy-(C1 -C6)alkyl, (C1 -C6)-alkylamino, ##STR62## and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R13 is hydrogen, phenyl or (C1 -C6)alkyl;
or R12 and R13, together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms that is neither the point of attachment of the spiro ring nor adjacent to it may optionally be replaced by oxygen, nitrogen or sulfur;
R14 and R15 are each independently selected from hydrogen, hydroxy, halo, amino, oxo (═O ), cyano, hydroxy-(C1 -C6)alkyl, (C1 -C6)alkoxy-(C1 -C6)alkyl, (C1 -C6)alkylamino, di-(C1 -C6)alkylamino, ##STR63## and the radicals set forth in the definition of R12 ; with the proviso that (a) when R14 and R15 are attached to the same carbon atom, then either each of R14 and R15 is independently selected from hydrogen, fluoro, (C1 -C6)alkyl, hydroxy-(C1 -C6)alkyl and (C1 -C6)alkoxy-(C1 -C6)alkyl, or R14 and R15, together with the carbon to which they are attached, form a (C3 -C6) saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; (b) R12 and R13 cannot both be hydrogen; (c) when R14 or R15 is attached to a carbon atom of X4 that is adjacent to the ring nitrogen, then R14 or R15, respectively, must be a substituent wherein the point of attachment is a carbon atom; and (d) neither R14 , R15 can form a ring with R13 ;
or a pharmaceutically acceptable salt thereof, effective in treating or preventing such condition.
2. A method according to claim 1, wherein the compound administered to said mammal is selected from the group consisting of:
(2S,3S)-3-(5-tert-butyl-2-methoxybenzyl)amino-2-(3-trifluoromethoxyphenyl)piperidine;
(2S,3S)-3-(2-isopropoxy-5-trifluoromethoxybenzyl)amino-2-phenyl-piperidine;
(2S,3S)-3-(2-ethoxy-5-trifluoromethoxybenzyl)amino-2-phenyl-piperidine;
(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)-amino-2-phenylpiperidine;
(2S,3S)-3-(-5-tert-butyl-2-trifluoromethoxybenzyl)amino-2-phenylpiperidine;
2-(diphenylmethyl)-N-(2-methoxy-5-trifluoromethoxy-phenyl)methyl-1-azabicyclo[2.2.2]octan-3-amine;
(2S,3S)-3-[5-chloro-2-(2,2,2-trifluoroethoxy)benzyl]amino-2-phenylpiperidine;
(2S,3S)-3-(5-tert-butyl-2-trifluoromethoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(2-isopropoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(2-difluoromethoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-2-phenyl-3-[2-(2,2,2-trifluoroethoxybenzyl)aminopiperidine; and
(2S,3S)-2-phenyl-3-(2-trifluoromethoxybenzyl)]aminopiperidine.
3. A method according to claim 1, wherein the compound administered to said mammal is selected from the group consisting of:
cis-3-(2-chlorobenzylamino)-2-phenylpiperidine;
cis-3-(2-trifluoromethylbenzylamino)-2-phenylpiperidine;
cis-3-(2-methoxybenzylamino)-2-(2-fluorophenyl)piperidine;
cis-3-(2-methoxybenzylamino)-2-(2-chlorophenyl)piperidine;
cis-3-(2-methoxybenzylamino)-2-(2-methylphenyl)piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-methoxyphenyl)piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-fluorophenyl)piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-chlorophenyl)piperidine;
cis-3-(2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(2-methoxybenzylamino)-2-(3-methylphenyl)piperidine;
cis-3-(2-methoxybenzylamino)-2-(4-fluorophenyl)piperidine;
cis-3-(2-methoxybenzylamino)-2-(3-thienyl)-piperidine;
cis-3-(2-methoxybenzylamino)-2-phenylazacyclo-heptane;
3-(2-methoxybenzylamino)-4-methyl-2-phenylpiperidine;
3-(2-methoxybenzylamino)-5-methyl-2-phenylpiperidine;
3-(2-methoxybenzylamino)-6-methyl-2-phenylpiperidine;
(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(5-carboethoxypent-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(6-hydroxy-hex-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(4-hydroxy-4-phenylbut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(4-oxo-4-phenylbut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(5,6-dihydroxyhex1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(5-fluoro-2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-[4-(4-fluorophenyl)-4-oxobut-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-[4-[4-fluorophenyl)-4-hydroxybut-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(2-methoxy-5-methylbenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(4-benzamidobut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(2-methoxynaphth-1-ylmethylamino)-2-phenylpiperidine;
(2S,3S)-3-(2-methoxybenzylamino)-1-(5-N-methylcarboxamidopent-1-yl)-2-phenylpiperidine;
(2S,3S)-1-(4-cyanobut-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-[4-(2-naphthamido)but-1-yl]-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(5-benzamidopent-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-1-(5-aminopent-1-yl)-3-(2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-3-(5-chloro-2-methoxybenzylamino)-2-phenylpiperidine;
(2S,3S)-3-(2,5-dimethoxybenzylamino)-2-phenylpiperidine;
cis-3-(3,5-difluoro-2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(4,5-difluoro-2-methoxybenzylamino)-2-phenylpiperidine;
cis-3-(2,5-dimethoxybenzylamino)-1-[4-(4-fluorophenyl)-4-oxobut-1-yl]-2-phenylpiperidine;
cis-3-(5-chloro-2-methoxybenzylamino)-1-(5,6-dihydroxyhex-1-yl)-2-phenylpiperidine;
cis-1-(5,6-dihydroxyhex-1-yl)-3-(2,5-dimethoxybenzylamino)-2-phenylpiperidine;
cis-2-phenyl-3-[-2-(prop-2-yloxy)benzylamino]piperidine;
cis-3-(2,5-dimethoxybenzyl)amino-2-(3-methoxyphenyl)piperidine hydrochloride;
cis-3-(5-chloro-2-methoxybenzyl)amino-2-(3-methoxyphenyl)piperidine dihydrochloride;
cis-3-(5-chloro-2-methoxybenzyl)amino-2-(3-chlorophenyl)piperidine dihydrochloride;
3-(2-methoxybenzylamino)-2,4-diphenylpiperidine;
cis-3-(2-methoxybenzylamino)-2-phenylpyrrolidine;
(2S,3S)-3-(5-ethyl-2-methoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(5-n-butyl-2-methoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(2-methoxy-5-n-propylbenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(5-isopropyl-2-methoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(5-s-butyl-2-methoxybenzyl)amino-2-phenylpiperidine;
(2S,3S)-3-(5-t-butyl-2-methoxybenzyl)amino-2-phenylpiperidine; and
(2S,3S)-3-(2-methoxy-5-phenylbenzyl)amino-2-phenylpiperidine.
US08/072,629 1993-06-04 1993-06-04 Pharmaceutical agents for treatment of emesis Expired - Lifetime US5393762A (en)

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US08/072,629 US5393762A (en) 1993-06-04 1993-06-04 Pharmaceutical agents for treatment of emesis
TW083103232A TW318791B (en) 1993-06-04 1994-04-12
PT94303467T PT627221E (en) 1993-06-04 1994-05-16 P ANTAGONIST SUBSTANCES FOR THE TREATMENT OF EMESE
DE69429208T DE69429208T2 (en) 1993-06-04 1994-05-16 Substance P antagonists used to treat vomiting
AT94303467T ATE209490T1 (en) 1993-06-04 1994-05-16 SUBSTANCE P ANTAGONISTS FOR THE TREATMENT OF VOMITING
DK94303467T DK0627221T3 (en) 1993-06-04 1994-05-16 Substance P antagonists for the treatment of emesis
EP94303467A EP0627221B1 (en) 1993-06-04 1994-05-16 Substance P antagonists for the treatment of emesis
ES94303467T ES2164088T3 (en) 1993-06-04 1994-05-16 ANTAGONISTS OF THE SUBSTANCE P FOR THE TREATMENT OF EMESIS.
IL10980294A IL109802A (en) 1993-06-04 1994-05-26 Pharmaceutical compositions containing n-substituted 2-methoxybenzylamines for treatment of emesis
CA002124990A CA2124990C (en) 1993-06-04 1994-06-02 Pharmaceutical agents for treatment of emesis
JP6121042A JP2671972B2 (en) 1993-06-04 1994-06-02 Drugs for the treatment of vomiting
MYPI94001422A MY115310A (en) 1993-06-04 1994-06-02 Substance p antagonists for the treatment of emesis
HU9401676A HU222243B1 (en) 1993-06-04 1994-06-03 Process for the preparation of pharmaceutical compositions containing piperidine or azabicyclooctane derivatives for treatment of emesis
AU64521/94A AU666077B2 (en) 1993-06-04 1994-06-03 Pharmaceutical agents for treatment of emesis
KR1019940012527A KR100190729B1 (en) 1993-06-04 1994-06-03 Pharmaceutical agents for treatment of emesis
CN94106917A CN1100535C (en) 1993-06-04 1994-06-03 Pharmaceutical agents for treatment of emesis
RU94020410A RU2135179C1 (en) 1993-06-04 1994-06-03 Method of treatment or prophylaxis of mammals and human with vomiting using some quinuclidine, piperidine, azanorbornane, ethylenediamine derivatives and related compounds
NZ260674A NZ260674A (en) 1993-06-04 1994-06-03 Use of an aminopiperidine or azabicyclo[2.2.2]octan-3-amine derivative for treating emesis in mammals
ZA943896A ZA943896B (en) 1993-06-04 1994-06-03 Pharmaceutical agents for treatment of emesis

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